By Annick VOGELS and Jean-Pierre FRYNS.
Center for Human, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
Microdeletions are often characterised by a complex clinical and behavioural phenotype resulting from the imbalance of normal dosage of genes located in that particular chromosomal segment.
In this review we include the present state of art and a delineation of the future approach to study the candidate genes in the microdeletion syndromes resulting from unequal homologous recombination at meiosis between duplicons: Velocardiofacial syndrome, Prader-Willi syndrome, Angelman syndrome, Neurofibromatosis type 1, Williams syndrome, Smith-Magenis syndrome and distal 8p deletion.
Microdeletion syndromes are defined as a group of clinically recognisable disorders characterised by a small (< 5Mb) deletion of a chromosomal segment spanning multiple disease genes, each potentially contributing to the phenotype independently . The genetic changes of microdeletions are often not detectable by the current band resolution using routine or high resolution karyotyping (2-5 Mb) but require the application of molecular cytogenetic techniques such as Fluorescence In Situ Hybridisation (FISH). FISH has now become the standard diagnostic approach for the commonly known microdeletions. The phenotype is the result of haploinsufficiency for specific genes in the critical interval. Clinically well described syndromes, for which the involvement of multiple disease genes has been established or is strongly suspected include Velocardiofacial syndrome (22q11 microdeletion), Williams syndrome (7q11 microdeletion), Neurofibromatosis type 1 (17q11 microdeletion), Smith-Magenis Syndrome (17p microdeletion) and 8p microdeletion syndrome. Correlations between chromosomal rearrangements and clinical manifestations, or genotype/ phenotype correlations, can provide essential information for the discovery of the causes of developmental effects . However, progress towards the identification of these developmental genes has been slow.
- The first step in the search for genotype/phenotype correlation is identifying the deletion size also called “the typically deleted region” (TDR) of the syndrome. It was found that each microdeletion syndrome has same-sized deletions in the majority of the patients. It was then suggested that there might be sequences at the breakpoints that are particularly prone to rearrangements.
- The second step in identifying genes in these microdeletions syndromes is to compare deletions sizes from different patients with the same microdeletion syndrome in order to establish the shortest region of deletion overlap (SRDO). Although more tractable than the larger size of the typical deleted region, these SRDO’s commonly encompass multiple genes and identifying the disease genes is still a surprisingly difficult task.
- A third common strategy to identify the essential genes that are involved in a particular syndrome, is traditional positional-cloning in patients with unusual deletions or rare translocations.
In this chapter we will review the microdeletion syndromes resulting from unequal homologous recombination at meiosis between duplicons that had a well described physical and behavioural phenotype before the discovery of their genetic aetiology. : Velocardiofacial syndrome, Prader-Willi syndrome, Angelman Syndrome, Neurofibromatosis type 1, Williams syndrome, Smith-Magenis syndrome and distal 8p deletion.
THE VELOCARDIOFACIAL SYNDROME
Clinical and behavioural phenotype
Velocardiofacial syndrome is the most frequent known interstitial deletion found in man with an incidence of 1 in 4000 live births . Most deletions are the result of a de novo event, although probably 5-10% are inherited . Several diagnostic labels have been used for this syndrome including Di George syndrome (DGS) , Conotruncal anomaly face syndrome or Takao syndrome . Shprintzen syndrome  and 22q11deletion syndrome .
The structures primarily affected in VCFS include the thymus, parathyroid gland, aortic arch, branchial arch arteries and face. These key clinical features are due to abnormal development of the third and fourth pharyngeal pouches during embryogenesis and are therefore classified as “the pharyngeal phenotype”. The other key clinical traits include learning difficulties, cognitive deficits, attention deficit disorders and psychiatric disorders  and are classified as “the neurobehavioral phenotype”. There is incomplete penetrance and therefore a marked variability in clinical expression between the different patients, making early diagnosis difficult . The physical phenotype is characterised by facial dysmorphism, palatal abnormalities, hypocalcemia, T-cell immunodeficiency and learning disabilities. Heart defects are present in 50-75% of the patients and are usually diagnosed in early infancy. Minor manifestations are usually associated including a history of polyhydramnios, signs of velopharyngeal insufficiency, minor facial anomalies, slender appearance of the fingers, constipation and hypotonia. Speech and language delay is one of the most consistent manifestations of VCFS in part related to the velopharyngeal insufficiency. Recurrent upper-airway and ear infections are common during infancy and early childhood. In adolescence there is a high risk for development of obesity and scoliosis (10%) .
Recent studies of the cognitive and psychoeducational profiles of children with 22q11deletion confirm a wide variation in intelligence, ranging from moderate mental retardation to average intelligence, with a mean full-scale IQ of about 70 [18,19]. Severe mental retardation is rare. The mean full-scale IQ in familial cases is lower compared to those with de novo cases [19,20], a finding which can be explained at least in part by the multifaceted origin of intelligence and by assortative mating. A possible relationship between 22q11deletion and a non-verbal learning disorder was suggested [21,22]. Common behavioural and temperamental characteristics include impulsiveness, disinhibition, shyness and withdrawal . A wide variety of child psychiatric disorders has been reported including attentions deficit disorder and rapidly cycling bipolar disorder in late childhood and adolescence , childhood schizophrenia [24,25] and mood disorders . Current estimates are that +/- 35 % of patients develop psychiatric disorders in adolescence or adulthood . There is a higher than expected rate of psychotic disorder, specifically schizophrenia, schizoaffective disorder and bipolar disorder, among adult persons diagnosed with VCFS [23,28].
Genes within the deletion
Numerous genes have been identified within the most commonly deleted region of 22q11.2.
In their search for genes, investigators have also sought for genes that might have a role in branchial arch or neural crest development . Several candidate genes have received particular attention (IDD/SEZI/LAN, GSCL, HIRA, UFD1L) but all proved to be negative for mutations in VCFS patients without a 22q11 microdeletion. COMT, the gene encoding for catechol-O-methyl transferase, has a crucial role in the metabolism of the neurotransmitter dopamine. Abnormal function of the dopaminergic pathways is considered to play a major role in schizophrenia . As the gene coding for COMT maps to 22q11, the COMT gene is considered a prime candidate gene for the etiology of schizophrenia in VCFS. It was therefore suggested that the common functional genetic polymorphism in the COMT gene, which results in a 3-to4-fold difference in COMT activity  may contribute to the etiology of psychiatric disorders. Two studies reported that in a population of patients with VCFS, there is an apparent association between the low-activity allele, COMT158met, on the non-deleted chromosome and the development of a bipolar spectrum disorder and, in particular, a rapid cycling form [45-47].
THE PRADER-WILLI SYNDROME AND THE ANGELMAN SYNDROME
Clinical and behavioural phenotype of the Prader-Willi syndrome
The Prader-Willi syndrome (PWS) is a complex multisystem disorder characterised by a variety of clinical features . The clinical phenotype is characterised by hyperphagia, childhood-onset- obesity, severe muscle hypotonia, a typical facies, hypogonadism with absence of a pubertal growth spurt, short stature, small hands and feet and delayed developmental milestones. The typical facial features include a small forehead, almond shaped eyes, micrognathia, a thin upper lip and down-turned corners of the mouth . The syndrome is now considered as a multistage disorder characterised by three different phases .
- The first, “the hypotonic phase”, is characterised by varying degrees of hypotonia during the neonatal period and early infancy, a weak cry, hypothermia, hypogenitalism and a poor suck reflex usually necessitating gavage feeding . During the first year, PWS children are defined as friendly, easy going and affectionate .
- The second phase, “the hyperphagic phase”, which usually starts between the ages of one and two, is characterised by a voracious appetite, hyperphagia, foraging for food, early onset of childhood obesity, physical inactivity, decreased pain sensitivity, disturbed thermoregulation, psychomotor retardation, speech articulation difficulties and cognitive dysfunction. Simultaneously, with the change in eating pattern, PWS individuals show significant maladaptive behavioural and emotional characteristics including temper tantrums, inappropriate social behaviour, automutilation (skin picking), stubbornness, mood lability, impulsivity, argumentativeness, anxiety and obsessive compulsive symptoms [67,68].
- The third phase ‘“adolescence and adulthood” is dominated by health problems secondary to obesity. These include scoliosis, dental problems, diabetes mellitus, hypertension, hypercholesterolemia, osteoporosis . About 10% of the adolescents and adults develop major psychiatric problems ranging from severe and agitated depression to psychotic episodes [70,71]. The psychotic episodes in PWS patients have many features in common including an acute onset, a polymorphous and fluctuating symptomatology with anxieties, agitation, abnormal beliefs and auditory hallucinations. These episodes are classified as acute cycloid psychosis .
Dysfunction of the hypothalamus may be the basis of a number of symptoms in the Prader-Willi syndrome. The fetal hypothalamus plays a major role in labour and hypothalamic dysfunction may explain the high proportion of children born prematurely or postmaturely. Abnormal LSH-releasing hormones are thought to be responsible for the decreased levels of sex hormones resulting in non-descended testes, undersized sex organs, amenorrhoea and insufficient growth during puberty. Growth hormone deficiency due to hypothalamic dysregulation contributes to the abnormal growth pattern, excess of body fat and deficit of lean body mass with consequent reduced energy expenditure. Hypothalamic disturbances cause aberrant control of body temperature and daytime hypersomnolence. The insatiable hunger and hyperphagia is probably a consequence of the decreased number of oxytocine neurones- the putative satiety neurones in the hypothalamic paraventricular nucleus .
Clinical and behavioural phenotype of the Angelman Syndrome
The typical facial features in Angelman syndrome (AS) include brachycephaly, microcephaly, a large mouth with widely spaced teeth, mandibular prognatism, midfacial hypoplasia, deep-set and blue eyes and hypopigmentation. This facial gestalt becomes apparent between the age of one and four years and there is a facial coarsening with increasing age. AS patients show truncal ataxia and hypotonia with hypertonia of the limbs and have a high risk for developing scoliosis. All patients have severe mental retardation with little or no development of active language. Jerky movements including tongue thrusting, mouthing and flapping when walking become apparent in the first years of life. The gait is slow, ataxic and stiff-legged with the characteristic posture of raised arms with flexed wrists and elbows. Paroxysms of easily provoked, prolonged laughter may start as early as 10 weeks. Hyperactivity and sleep disorders are common in childhood. AS individuals are fascinated by water, mirrors and plastic. Epileptic seizures occur in 80% of the patients with an onset varying between one month and 5 years. A diversity of seizures can be observed, ranging from atypical absence seizures, tonic-clonic seizures, myoclonic seizures, and tonic seizures to status epilepticus. They are difficult to control. The EEG patterns seen in AS are very characteristic and are seen in patients with and without seizures and may play an important diagnostic role in the appropriate clinical context . Neuroimaging studies are normal. Cerebral atrophy and ventricular dilatation are seen in a minority of the patients.
Molecular genetics of the Angelman and the Prader-Willi syndrome
PWS and AS result from loss of paternal or maternal expression, respectively, of genes located on the human chromosome 15q11-13 region . Different molecular mechanisms leading to this loss of expression have been identified, including microdeletions, intragenic mutations, uniparental disomy and imprinting defects:
A. Microdeletions in PWS and AS
75% of the PWS patients and 70% of the AS patients have large chromosomal deletions of +/- 4 Mb of the same chromosomal 15q11-13 region, the typically deleted region (TDR). In PWS there is a deletion on the paternally inherited chromosome, while in Angelman there is a deletion on the maternally inherited chromosome.
B. Single gene mutations in PWS and AS
There are no known PWS patients with a single gene mutation, suggesting that PWS is a continuous gene syndrome. In 4 % of the cases, Angelman is caused by mutations in the Ubiquitin ligase gene, UBE3A [76,77].
C. Uniparental disomy in PWS and AS
Uniparental disomy occurs in 24% of the PWS patients (maternal disomy) and in 3-5% of AS patients (paternal disomy). The most likely explanation is trisomy 15 rescue, suggested by the observation of trisomy 15 mosaicism in patients with unusual PWS manifestations [78-80]
D. Imprinting defects in PWS and AS
The imprinting centre (IC) regulates the erasure, establishment and maintenance of paternal and maternal imprinted genes. It has been mapped to the SNURF-SNRPN locus and presents with a bipartite structure overlapping the SNRPN promotor. The exon alpha SNRPN promotor is found within a CpG island that is completely methylated on the maternal chromosome and completely unmethylated on the paternal chromosome.
IC defects are found in 2 % of the AS cases and in less than 1 % of the PWS cases.
Genes within the deletion for PWS
In PWS patients, the typically deleted region on the paternal chromosome is 4Mb and the PWS-SRO (smallest region of overlap) is 4,3 kb .The common deletion includes a large cluster of imprinted genes (2-3Mb) and a non-imprinted domain (1-2Mb) [89,97]. A cluster of paternally expressed genes has been mapped to the PWS region: SNURF-SNRPN (small ribonucleoprotein N upstream reading frame-small ribonucleoprotein N), MKRN3 (makorin ring finger protein), IPW (imprinted gene in the PWS region gene), MAGEL2 (melanoma antigen-like gene2), and NDN (necdin) [75,98]. It is not clear if PWS is caused by the loss of expression of a single imprinted gene or multiple genes. Two strong candidates for PWS are NDN and MAGEL2. The human NDN is a good candidate due to its expression in the nervous system and the observation that it is absent in PWS patients . MAGEL2 is expressed predominantly in the brain and in several foetal tissues.
Genes within the deletion for AS
In AS patients, the common deletion on the maternal chromosome also spans a 4 Mb interval and includes a cluster of imprinted and a non-imprinted domain . The UBE3A gene (ubiquitin ligase 3) was mapped to the AS critical region in 1994 and its role in AS was corroborated by the observation that point mutations in UBE3A are present in a small (4-6%) fraction of the AS patients [76,77,102-104].
Genotypic / phenotypic correlations with these different genetic causes were identified. Individuals with a deletion show the classic signs of AS . A milder phenotype is found among the cases with paternal UPD. These AS individuals have better growth, less hypopigmentation, more subtle facial changes, walk at earlier ages, have less severe or frequent seizure disorders, less ataxia and a greater facility with rudimentary communication such as signing and gesturing [120,121]. AS patients with imprinting mutations have a less severe seizure disorder, show milder microcephaly and less hypopigmentation. Milder epilepsy is noted in AS with UBE3A mutations . Further refinement of the phenotype/ genotype correlation will progressively improve the gene-behaviour understanding .
A correlation between psychiatric disorders in PWS and uniparental disomy has recently been reported . If this finding is confirmed, imprinted genes outside the typically deleted region on the paternal or the maternal chromosome may contribute to the psychiatric phenotype.
The neurofibromatoses (NF) are a heterogeneous group of hereditary neurocutaneous disorders clinically characterised by abnormalities in tissues that are predominantly derived from the neural crest . In the past few years, clinical and genetic studies have led to the identification of two separate entities as the major NF forms: neurofibromatosis type 1 (NF 1) and neurofibromatosis type 2 (NF 2). Final confirmation that NF 1 and NF 2 are different disorders has been achieved by the identification of the two responsible genes, the NF1 gene located on chromosome 17q11.2  and the NF2 gene located on chromosome 22q12.2 . NF1 is usually caused by a mutation in the NF1 gene, but in an estimated 5-10% of cases NF1 is the result of a microdeletion in the 17q11.2 region.
Clinical and behavioural phenotype
Café-au-lait spots are the most typical skin abnormality in Neurofibromatosis 1 (NF1). They usually appear during the first year of life and are present in all affected children by the age of five . Freckling, especially skin fold freckling in the axillar and inguinal regions, appear later in age. Neurofibromas often make their appearance just before or during adolescence. They tend to increase with age and during pregnancy suggesting that their presence may be hormone responsive .
- Cutaneous neurofibromas are complex benign peripheral nerve tumours consisting of a mixture of Schwann cells, perineural cells, fibroblasts and mast cells. In general, they are not painful but may become a cosmetic problem.
- Spinal neurofibromas may be very painful and lead to neurological dysfunction.
- Plexiform neurofibromas consist of a proliferation of cells in the nerve sheets extending across the length of nerve, and involving multiple nerve fascicles . They appear at a very young age.
- Lisch noduli are pigmented hamartomas of melanocytic origin located in the iris. They may vary in appearance depending on the underlying colour of the iris. Their prevalence increases with age, to 99 % in adults.
- Optic pathway gliomas (OPG) and brains stem gliomas are the predominant intracranial neoplasms associated with NF 1  and are classified as pilocytic astrocytomas. OPG remain asymptomatic in the majority of the cases. Possible symptoms associated with OPG are prooptosis, precocious puberty and diminished vision . The greatest risk for development of OPG in NF1 is during the first 6 years of life .
There is an increased risk of developing NF1 related malignancies (lifetime risk 2-5%) [137,138]. These malignancies mainly include malignant peripheral nerve sheat tumours (MPNSTs), malignant CNS tumours, pheochromocytomas, rhabdomyosarcomas and juvenile myelocytic leukaemia (JCML) . MPNSTs arise frequently from plexiform neurofibromas in young NF1 adults. They are particularly aggressive and often fatal. The first symptoms are neurological deficits or rapid growth enlargement or pain in an existing plexiform neurofibroma. The main first manifesting symptoms of pheochromocytoma are secondary hypertension with headaches, palpitation and flushing. Children with chronic myelotic leukaemia (JCML) have hepatosplenomegaly, leucocytosis and absence of the Philadelphia chromosome .
Unidentified bright objects (UBOs) are well circumscribed round to oval spots seen on T2-weighed brain MRI scans. Their clinical course is benign and they usually disappear with age [141-143]. Some studies suggest a correlation between UBOs and some aspects of cognitive functioning [144-147], but these findings are not confirmed by others [148,149]. NF1 specific osseous lesions include pseudoarthrosis of the tibia, sphenoid wing dysplasia, bowing or thinning of the cortex of the long bones with or without pseudoarthrosis .
The mean total intelligent quotient in children with NF1 ranges from 88 to 94 [149,151,152], whereas only 4-8 % have mental retardation defined as full-scale IQ below 70 . There is no specific characteristic profile of learning disability in NF1 . The reported frequency of learning disabilities, defined as a significant discrepancy between ability and achievement, ranges between 30 and 65 % [153,154]. Evidence of Attention Deficits has been reported in one third of NF children , but the incidence of attention deficit hyperactivity disorder is not known and further research is needed in this area. Motor coordination is frequently impaired. Social and emotional problems including social problems, anxieties, depression, withdrawal, thought problems, somatic complaints, and aggressive behaviour are reported in children with NF1 . A significant psychopathology was found in a twelve-year follow-up study of adult patients with NF1. One third of the patients was affected by a psychiatric disease, 21%by dysthymia . It is not clear whether these characteristics are a primarily genetic affect or whether they are secondary to the impact of the somatic deficits on the psychological and emotional well being.
Molecular genetics of the NF1 microdeletions
Mechanisms leading to the deletion
About 80% of the NFI microdeletions are of maternal origin  and have a size of 1.5 Mb. Most cases have a de novo deletion . The deletion breakpoints cluster in flanking duplicated sequences called 3 NF-REPs [160,161]. NF 1 microdeletions result from an unequal cross over in maternal meiosis 1, mediated by misalignment of the flanking NF1-REPs. The NF1-repeats are direct repeats that span 100-150kb and contain several pseudogenes and 4 expressed sequence tags (EST) . Recently, it was demonstrated that most of the recombination events occur in a discrete 2 kb recombination hotspot within each of these flanking NF1-REPs . The finding of a recombination hotspot for NFI microdeletions and the development of a deletion specific PCR assay have significant implications for future research
Genes within the deletion
The detection of the NF1 gene has preceded the discovery of the microdeletions as a cause of NF 1. Identification of translocation breakpoints in different patients permitted the construction of physical map and allowed cloning of the NF1 gene . Since then, a large variety of mutations has been found. The identification of the encoded protein was the first clue to the molecular basis of NF 1. The NF 1 encoded protein, neurofibromin, is composed of 2818 aminoacids . A central 360 amino acid region of the predicted protein product shows homology to members of the Ras-GTPase-activating (Ras-GAP) family of proteins. The GAP related domain (NF1-GRD) of neurofibromin represents so far the only known functional domain of the NF1 gene. The function of the remainder of the molecule is not known.
Genotype/ phenotype correlation
Until now, it is not possible to predict the clinical presentation in individual NFI patients based on the localisation and the type of mutation. Only in NF1 patients with a NF1 gene deletion a distinct phenotype seems to emerge. In 5-10 % of NF1patients, an entire gene deletion has been described. In about 80% of the cases the deletion occurs de novo and is of maternal origin [158,185,186]. Most patients with NF1 microdeletions present a distinct phenotype characterised by the presence of a variable facial dysmorphism: coarse face, facial asymmetry, ptosis, prominent forehead, hypertelorism, thick prominent nasal tip and “Noonan-like” face. These patients have mild mental retardation, skeletal abnormalities and hypermobility of the joints. An important clinical feature present in NF1 deletion patients is the increased number of neurofibromas and their presence at a young age. An interesting hypothesis is that deletions of (an) unidentified nearby gene(s) predispose to the development of neurofibromas, (a) gene(s) that could have a tumour suppressor function. The role of a putative co-deleted gene has been difficult to asses because the number of patients with a microdeletion is relatively small and the information regarding number and age of onset of neurofibromas and deletionsize is not always evaluated or reported in the same way. The lower IQ in the group of patients with a microdeletion, compared with the total group of NF1 individuals, suggests that some dosage sensitive genes in the microdeletion region are important for cognitive functioning. An overgrowth syndrome has been reported in patients carrying the NF1 gene deletion . The presence of large hands and feet has also been described in several NF1 deletion patients. NF1 microdeletions may predispose patients to develop malignant tumours . In benign neurofibromas loss of heterozygosity has been observed for markers on the long arm of chromosome 17 reflecting a “second hit” of the NF1 gene . In a patient with a microdeletion in the NF1 region a “second hit” affecting the normal chromosome 17 homologue could at the same time inactivate the NF1 gene and unknown tumour suppressor genes in the deleted region.
So far, most of the cases described in the literature carrying NF1 microdeletions are young patients. Several of the clinical signs are expected to appear only at puberty or later (neurofibromas and malignancies), making it difficult to draw any conclusion concerning the severity of the phenotype in several of these patients. Prospective studies will be able to better estimate the effect of a deletion on certain clinical manifestations such as early age of onset of cutaneous neurofibromas, malignancies and mental retardation.
THE WILLIAMS SYNDROME
Clinical and behavioural phenotype
The incidence of Williams syndrome (WBS) is estimated at approximately 1 per 20.000. Individuals with WBS have a distinct facial dysmorphism including periorbital fullness, stellate pattern of the irides, anteverted nares, long philtrum and prominent full lips. Cardiovascular anomalies include supravalvular aortic stenosis (SVAS), peripheral pulmonary artery stenosis and pulmonic valvular stenosis. Other symptoms include dental problems such as malocclusion, small and missing teeth, growth deficiency, hypercalcemia, vomiting, constipation, colic in infancy, impaired visual acuity, musculoskeletal abnormalities, hyperacusis and a hoarse low voice. They show an intriguing behavioural phenotype with mental retardation, a specific neuropsychological profile and a distinct socio-affective profile. Most individuals with WBS function in the mild range of mental retardation with IQ’s averaging about 60. The neuropsychological profile includes strengths in face perception and face recognition memory, affective attainment, short term auditory memory and select aspects of language. They show “cocktail party” verbal abilities, i.e. verbal abilities that are superficially quite intact but formal assessment shows overall delayed language abilities . Along with the superficial strengths in language abilities, they show weaknesses in visuospatial, motor, visuomotor integration and arithmetic skills. Remarkable are the large differences in the visual perception of faces (visuofeature domain) and the visual perception of spatial material (visuospatial). This duality in functioning in “space and face” in WBS can be explained by functional segregation of visual processes in brain MRI studies . A possible physiological base for the strength in language and music skills has been found in those recent MRI studies. Alteration in functions of the primary auditory cortex may explain the high rate of hyperacusis and could be related to the language and music perceptual processes. Future research will help to learn more about the function of the genes in the critical WS region and will help to delineate the relationship between genes, brain and behaviour.
Mechanisms leading to the deletion
Most deletions in WBS patients are of a consistent size of 1.6Mb. Haplotype analysis demonstrated that unequal meiotic recombination underlie the formation of a high proportion of 7q11.23 deletions . It was found that the WS deletion is flanked by low-copy repeats [193,194].. These duplicons are approximately 400kb long and consist of blocks of nearly identical DNA occurring in the same or opposite directions. They contain transcribed genes, pseudogenes and putative telomere associated repeats. . The majority of the WBS region interstitial deletions have been shown to be due to unbalanced interchromosomal recombination during meiosis, fewer are seen due to intrachromosomal recombination . Recently, Osborne et al.  found that not only deletions but also inversions can be mediated by the repeating units flanking the interval. In at least three individuals, the inversion seems to be associated with a subset of the WBS phenotypic spectrum. Osborne et al  suggested that the breakpoints interrupts or affects the expression of functional genes located within the duplicon. Further research is needed to confirm this. In 4 of the 12 families with a proband carrying the WBS deletion, this inversion was found in the parent transmitting the disease related chromosome suggesting that this inversion may predispose to the formation of deletion .
Genes within the deletion
In 1993, Ewart et al demonstrated linkage of isolated familial supravalvular aortastenosis (SVAS) to the elastine gene (ELN) . Since SVAS is also a component of WBS, they examined WBS for mutations in the ELN. The WBS patients were found to have large deletions encompassing the entire ELN gene, suggesting that WS may be due to a microdeletion of chromosomal region 7q11.23. Analysis of the region surrounding the ELN demonstrated that in more than 95% of the cases there is defined 1.5 Mb deletion. For the remaining individuals with clinical WBS, there is no detectable chromosomal rearrangement. Deletions occur with approximately equal frequency on the maternal and the paternally derived chromosome. At least 17 genes have been identified within this commonly deleted interval [196-198]. Vascular stenosis including supravalvular aorta stenosis is caused by haploinsufficiency of ELN.
Genotype/ phenotype correlation
Despite the number of genes commonly deleted none except ELN has been definitively shown to contribute to any of the clinical or behavioural symptoms and until now, the molecular base of the great variety in the clinical and behavioural phenotype in WBS remains unknown.
THE SMITH MAGENIS SYNDROME
Clinical and behavioural phenotype
Intelligence in SMS patients is varying from borderline to profound mental retardation. The degree of retardation is mostly moderate. Children with SMS show a particular pattern of behaviour that can be a useful clue to diagnosis. Infants are very sociable with appealing smiles and need to be waked for feeding . The most characteristic features in children include neurobehavioral abnormalities such as aggressive and self-injurious behaviour (SIB) and significant sleep disturbances and stereotypical behaviours . Behaviour problems include disobedience, hyperactivity, tantrums, attention seeking, sleep distortion, lability, property destruction, impulsivity, bed wetting and argumentative behaviour . SIB is frequent and reported in 67 % to 92% of all patients and includes head banging, self-hitting and hand, finger and wrist biting, nose or ear picking, onychotillomania, polyembolokoilomania . With increasing age and ability, the overall prevalence of SIB as well as the number of different types of SIB are increasing . Sleeping difficulties are reported in 65% to 75% of the patients and include difficulties falling asleep, frequent awakening, shortened sleep cycles and excessive daytime sleepiness . Stereotypical behaviours are an important clinical symptom in the diagnosis. Many SMS persons show self-hugging, behaviour and spasmodic upper body squeeze . Autistic characteristics are also reported [207,212,213]. The disturbed sleep pattern and behaviour problems correlate with a disturbed circadian rhythm in melatonin [214,215]. The abnormalities in the circadian rhythm of melatonin could be secondary to aberrations in the production, secretion, distribution or metabolism of melatonin. It was suggested that haploinsufficiency for a circadian gene mapping to chromosome 17p11.2 may cause the inversions of the circadian rhythm of melatonin in SMS.
Mechanisms leading to the deletion 
Most patients have a 5 Mb common deletion of 17p11.2 . The deletion in the 17p11.2 band in SMS patients occurs between two flanking repeat gene clusters .
Genes within the deletion
It is still unclear if the SMS phenotype is caused by the fusion of different genes from the flanking repeat gene clusters or by the loss of one or multiple genes in the context of a contiguous gene syndrome .
THE 8P DELETION SYNDROME
Clinical and behavioural phenotype
The finding that most cases of 8p interstitial deletion have been published only in the recent years suggests that this condition is more frequent than previously thought. The condition is associated with heart defects, typically in the form of an AVSD [221,222]. Other major manifestations include microcephaly, intrauterine growth retardation, mental retardation and a characteristic behavioural pattern. The behaviour is described as sudden and extreme outbursts of aggressiveness accompanied by destructive behaviour, low frustration tolerance, oppositional behaviour, hyperactivity and poor concentration .
Mechanisms leading to the deletion
Recently, it was demonstrated that unequal crossover between two olfactory receptor (OR) gene clusters in 8p is responsible for the formation of intrachromosomal rearrangements involving 8p. The olfactory OR-gene superfamily is the largest in the mammalian genomes. Several of the human OR genes appear in clusters with >10 members located on almost all human chromosomes .
Different rearrangements are associated with the distal 8p region including inv dup(8p) , del (8p23.1) , small marker chromosome der(8) (p23-pter)  and inv(8p). The type of rearrangement is predominantly defined by the orientation of recombining duplicons and the number of crossovers .
Genes within the deletion
In most patients a uniform interstitial deletion of +/- 6 Mb in 8p23.1 is detected [224,226,228,229]. Devriendt et al. performed genotype-phenotype correlation in nine unrelated patients with a de novo del 8p. Three patients with a small deletion and a partial phenotype not including heart defects lead to the delineation of a 8p heart-defect-critical region (HDCR8p) spanning 10 cM [226,229]. Both authors suggested the transcription factor GATA4 as a candidate gene. Additional observations  excluded a major role for GATA 4 in these congenital heart defects. The same author narrowed the HDCR8p and showed that haploinsufficiency for a gene between markers WI-8327 and D8S1825 is critical for heart development
Detailed description of the physical and behavioural phenotype of microdeletion syndromes, genotype/phenotype correlation and clinical and molecular examination of patients with rare translocations or deletions enable identification of developmental genes. Further studies of the duplicons flanking these microdeletions will provide more insight in the mechanism of their formation, and their possible effect on the genes within the microdeletion. The study of animal models has become a powerful tool to explore further the molecular and etiological basis of these microdeletion disorders. Engineering small deletions and duplications can be used to find the gene responsible for a haploinsufficient phenotype and to give insight into the embryological base of the disorder. The results of these investigations are going to have a major impact on human genetics.
1. Shaffer, L.G., Ledbetter, D.H., and Lupski, J.R. 2001, Molecular cytogenetics of contiguous gene syndromes: mechanisms and consequences of gene dosage imbalance. In: The Metabolic & Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle (Eds.), McGraw-Hill, Medical Publishing Division, New York, St. Louis, San Francisco, Auckland, Bogota, Caracas, Lisbon, London, Madrid, Mexico City, Milan, Montreal, New Delhi, San Juan, Singapore, sudney, Tokyo, Toronto, 1291.
2. Schmickel, R.D. 1986, Contiguous gene syndromes: a component of recognizable syndromes. J. Pediatr., 109, 231.
3. Emanuel, B.S., and Shaikh, T.H. 2001, Segmental duplications: an 'expanding' role in genomic instability and disease. Nat. Rev. Genet., 2, 791.
4. Emanuel, B.S., McDonald-McGinn, D., Saitta, S.C., and Zackai, E.H. 2001, The 22q11.2 deletion syndrome. Adv. Pediatr., 48, 39.
5. Shaffer, L.G., and Lupski, J.R. 2000, Molecular mechanisms for constitutional chromosomal rearrangements in humans. Annu. Rev. Genet., 34, 297.
6. Fan, Y.S., Siu, V. M., Jung, J.H., Farrell, S.A., and Cote, G.B. 2001, Direct duplication of 8p21.3®p23.1: a cytogenetic anomaly associated with developmental delay without consistent clinical features. Am. J. Med. Genet., 103, 231.
7. Ji, Y., Eichler, E.E., Schwartz, S., and Nicholls, R.D. 2000, Structure of chromosomal duplicons and their role in mediating human genomic disorders. Genome Res., 10, 597.
8. Lupski, J.R. 1998, Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet., 14, 417.
9. Osborne, L.R., Li, M., Pober, B., Chitayat, D., Bodurtha, J., Mandel, A., Costa, T., Grebe, T., Cox, S., Tsui, L.C., and Scherer, S.W. 2001, A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat. Genet., 29, 321.
10. Lindsay, E.A. 2001, Chromosomal microdeletions: dissecting del22q11 syndrome. Nat. Rev. Genet., 2, 858.
11. Scambler, P.J. 2000, The 22q11 deletion syndromes. Hum. Mol. Genet., 9, 2421.
12. Devriendt, K., Fryns, J.P., Mortier, G., van Thienen, M.N., and Keymolen, K. 1998, The annual incidence of DiGeorge/velocardiofacial syndrome. J. Med. Genet., 35, 789.
13. Di George, A. 1965, A new concept of the cellular basis of immunity. J. Pediatr., 67, 907.
14. Burn, J., Takao, A., Wilson, D., Cross, I., Momma, K., Wadey, R., Scambler, P., and Goodship, J. 1993, Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11. J. Med. Genet., 30, 822.
15. Shprintzen, R.J., Goldberg, R. B., Lewin, M. L., Sidoti, E.J., Berkman, M.D., Argamaso, R. V., and Young, D. 1978, A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J., 15, 56.
16. Swillen, A., Vogels, A., Devriendt, K., and Fryns, J.P. 2000, Chromosome 22q11 deletion syndrome: update and review of the clinical features, cognitive-behavioral spectrum, and psychiatric complications. Am. J. Med. Genet., 97, 128.
17. Vantrappen, G., Devriendt, K., Swillen, A., Rommel, N., Vogels, A., Eyskens, B., Gewillig, M., Feenstra, L., and Fryns, J.P. 1999, Presenting symptoms and clinical features in 130 patients with the velo- cardio-facial syndrome. The Leuven experience. Genet. Couns., 10, 3.
18. Moss, E.M., Batshaw, M.L., Solot, C.B., Gerdes, M., McDonald-McGinn, D.M., Driscoll, D.A., Emanuel, B.S., Zackai, E.H., and Wang, P.P. 1999, Psychoeducational profile of the 22q11.2 microdeletion: A complex pattern. J. Pediatr., 134, 193.
19. Swillen, A., Devriendt, K., Legius, E., Eyskens, B., Dumoulin, M., Gewillig, M., and Fryns, J.P. 1997, Intelligence and psychosocial adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS. J. Med. Genet., 34, 453.
20. Gerdes, M., Solot, C., Wang, P.P., Moss, E., LaRossa, D., Randall, P., Goldmuntz, E., Clark, B.J., III, Driscoll, D.A., Jawad, A., Emanuel, B.S., McDonald-McGinn, D.M., Batshaw, M.L., and Zackai, E.H. 1999, Cognitive and behavior profile of preschool children with chromosome 22q11.2 deletion. Am. J. Med. Genet., 85, 127.
21. Rourke, B.P. 1995, Syndrome of Nonverbal Learning Disabilities: Neurodevelopmental Manifestations, Guilford Press, New York.
22. Swillen, A., Vandeputte, L., Cracco, J., Maes, B., Ghesquiere, P., Devriendt, K., and Fryns, J.P. 1999, Neuropsychological, learning and psychosocial profile of primary school aged children with the velo-cardio-facial syndrome (22q11 deletion): evidence for a nonverbal learning disability? Neuropsychol. Dev. Cogn Sect. C. Child Neuropsychol., 5, 230.
23. Papolos, D.F., Faedda, G.L., Veit, S., Goldberg, R., Morrow, B., Kucherlapati, R., and Shprintzen, R.J. 1996, Bipolar spectrum disorders in patients diagnosed with velo-cardio- facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am. J. Psychiatry, 153, 1541.
24. Usiskin, S.I., Nicolson, R., Krasnewich, D.M., Yan, W., Lenane, M., Wudarsky, M., Hamburger, S.D., and Rapoport, J.L. 1999, Velocardiofacial syndrome in childhood-onset schizophrenia. J. Am. Acad. Child Adolesc. Psychiatry, 38, 1536.
25. Yan, W., Jacobsen, L.K., Krasnewich, D.M., Guan, X.Y., Lenane, M.C., Paul, S.P., Dalwadi, H.N., Zhang, H., Long, R.T., Kumra, S., Martin, B.M., Scambler, P.J., Trent, J.M., Sidransky, E., Ginns, E.I., and Rapoport, J. L. 1998, Chromosome 22q11.2 interstitial deletions among childhood-onset schizophrenics and "multidimensionally impaired". Am. J. Med. Genet., 81, 41.
26. Arnold, P.D., Siegel-Bartelt, J., Cytrynbaum, C., Teshima, I., and Schachar, R. 2001, Velo-cardio-facial syndrome: Implications of microdeletion 22q11 for schizophrenia and mood disorders. Am. J. Med. Genet., 105, 354.
27. Cohen, E., Chow, E.W., Weksberg, R., and Bassett, A.S. 1999, Phenotype of adults with the 22q11 deletion syndrome: A review. Am. J. Med. Genet., 86, 359.
28. Pulver, A.E., Nestadt, G., Goldberg, R., Shprintzen, R.J., Lamacz, M., Wolyniec, P. S., Morrow, B., Karayiorgou, M., Antonarakis, S.E., and Housman, D. 1994, Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J. Nerv. Ment. Dis., 182, 476.
29. Bassett, A.S., Hodgkinson, K., Chow, E.W., Correia, S., Scutt, L.E., and Weksberg, R. 1998, 22q11 deletion syndrome in adults with schizophrenia. Am. J. Med. Genet., 81, 328.
30. Gothelf, D., Frisch, A., Munitz, H., Rockah, R., Aviram, A., Mozes, T., Birger, M., Weizman, A., and Frydman, M. 1997, Velocardiofacial manifestations and microdeletions in schizophrenic inpatients. Am. J. Med. Genet., 72, 455.
31. Bassett, A.S., and Chow, E.W. 1999, 22q11 deletion syndrome: a genetic subtype of schizophrenia. Biol. Psychiatry, 46, 882.
32. Carlson, C., Sirotkin, H., Pandita, R., Goldberg, R., McKie, J., Wadey, R., Patanjali, S.R., Weissman, S.M., Anyane-Yeboa, K., Warburton, D., Scambler, P., Shprintzen, R., Kucherlapati, R., and Morrow, B.E. 1997, Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am. J. Hum. Genet., 61, 620.
33. Edelmann, L., Pandita, R.K., and Morrow, B. E. 1999, Low-copy repeats mediate the common 3-Mb deletion in patients with velo- cardio-facial syndrome. Am. J. Hum. Genet., 64, 1076.
34. Baumer, A., Dutly, F., Balmer, D., Riegel, M., Tukel, T., Krajewska-Walasek, M., and Schinzel, A.A. 1998, High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions. Hum. Mol. Genet., 7, 887.
35. Budarf, M.L., and Emanuel, B.S. 1997, Progress in the autosomal segmental aneusomy syndromes (SASs): single or multi-locus disorders? Hum. Mol. Genet., 6, 1657.
36. Budarf, M.L., Collins, J., Gong, W., Roe, B., Wang, Z., Bailey, L.C., Sellinger, B., Michaud, D., Driscoll, D.A., and Emanuel, B.S. 1995, Cloning a balanced translocation associated with DiGeorge syndrome and identification of a disrupted candidate gene. Nat. Genet., 10, 269.
37. Levy, A., Demczuk, S., Aurias, A., Depetris, D., Mattei, M.G., and Philip, N. 1995, Interstitial 22q11 microdeletion excluding the ADU breakpoint in a patient with DiGeorge syndrome. Hum. Mol. Genet., 4, 2417.
38. Kurahashi, H., Nakayama, T., Osugi, Y., Tsuda, E., Masuno, M., Imaizumi, K., Kamiya, T., Sano, T., Okada, S., and Nishisho, I. 1996, Deletion mapping of 22q11 in CATCH22 syndrome: identification of a second critical region. Am. J. Hum. Genet., 58, 1377.
39. Kurahashi, H., Tsuda, E., Kohama, R., Nakayama, T., Masuno, M., Imaizumi, K., Kamiya, T., Sano, T., Okada, S., and Nishisho, I. 1997, Another critical region for deletion of 22q11: a study of 100 patients. Am. J. Med. Genet., 72, 180.
40. McQuade, L., Christodoulou, J., Budarf, M., Sachdev, R., Wilson, M., Emanuel, B., and Colley, A. 1999, Patient with a 22q11.2 deletion with no overlap of the minimal DiGeorge syndrome critical region (MDGCR). Am. J. Med. Genet., 86, 27.
41. O'Donnell, H., McKeown, C., Gould, C., Morrow, B., and Scambler, P. 1997, Detection of an atypical 22q11 deletion that has no overlap with the DiGeorge syndrome critical region. Am. J. Hum. Genet., 60, 1544.
42. Rauch, A., Pfeiffer, R.A., Leipold, G., Singer, H., Tigges, M., and Hofbeck, M. 1999, A novel 22q11.2 microdeletion in DiGeorge syndrome. Am. J. Hum. Genet., 64, 659.
43. Kleinjan, D.J., and van Heyningen, V. 1998, Position effect in human genetic disease. Hum. Mol. Genet., 7, 1611.
44. Goldstein, M., and Deutch, A.Y. 1992, Dopaminergic mechanisms in the pathogenesis of schizophrenia. FASEB J., 6, 2413.
45. Lachman, H.M., Morrow, B., Shprintzen, R., Veit, S., Parsia, S.S., Faedda, G., Goldberg, R., Kucherlapati, R., and Papolos, D.F. 1996, Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am. J. Med. Genet., 67, 468.
46. Kimber, W.L., Hsieh, P., Hirotsune, S., Yuva-Paylor, L., Sutherland, H.F., Chen, A., Ruiz-Lozano, P., Hoogstraten-Miller, S.L., Chien, K.R., Paylor, R., Scambler, P.J., and Wynshaw-Boris, A. 1999, Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse. Hum. Mol. Genet., 8, 2229.
47. Kirov, G., Murphy, K.C., Arranz, M.J., Jones, I., McCandles, F., Kunugi, H., Murray, R.M., McGuffin, P., Collier, D.A., Owen, M.J., and Craddock, N. 1998, Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder. Mol. Psychiatry, 3, 342.
48. Botta, A., Lindsay, E.A., Jurecic, V., and Baldini, A. 1997, Comparative mapping of the DiGeorge syndrome region in mouse shows inconsistent gene order and differential degree of gene conservation. Mamm. Genome, 8, 890.
49. Puech, A., Saint-Jore, B., Funke, B., Gilbert, D.J., Sirotkin, H., Copeland, N.G., Jenkins, N.A., Kucherlapati, R., Morrow, B., and Skoultchi, A.I. 1997, Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization. Proc. Natl. Acad. Sci. U. S. A, 94, 14608.
50. Sutherland, H.F., Kim, U.J., and Scambler, P.J. 1998, Cloning and comparative mapping of the DiGeorge syndrome critical region in the mouse. Genomics, 52, 37.
51. Lindsay, E.A., Botta, A., Jurecic, V., Carattini-Rivera, S., Cheah, Y.C., Rosenblatt, H.M., Bradley, A., and Baldini, A. 1999, Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature, 401, 379.
52. Puech, A., Saint-Jore, B., Merscher, S., Russell, R.G., Cherif, D., Sirotkin, H., Xu, H., Factor, S., Kucherlapati, R., and Skoultchi, A.I. 2000, Normal cardiovascular development in mice deficient for 16 genes in 550 kb of the velocardiofacial/DiGeorge syndrome region. Proc. Natl. Acad. Sci. U. S. A, 97, 10090.
53. Gogos, J.A., Morgan, M., Luine, V., Santha, M., Ogawa, S., Pfaff, D., and Karayiorgou, M. 1998, Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc. Natl. Acad. Sci. U. S. A, 95, 9991.
54. Merscher, S., Funke, B., Epstein, J.A., Heyer, J., Puech, A., Lu, M.M., Xavier, R.J., Demay, M.B., Russell, R.G., Factor, S., Tokooya, K., Jore, B.S., Lopez, M., Pandita, R.K., Lia, M., Carrion, D., Xu, H., Schorle, H., Kobler, J.B., Scambler, P., Wynshaw-Boris, A., Skoultchi, A.I., Morrow, B.E., and Kucherlapati, R. 2001, TBX1 is responsible for cardiovascular defects in velo-cardio- facial/DiGeorge syndrome. Cell, 104, 619.
55. Jerome, L.A., and Papaioannou, V.E. 2001, DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat. Genet., 27, 286.
56. Paylor, R., McIlwain, K.L., McAninch, R., Nellis, A., Yuva-Paylor, L.A., Baldini, A., and Lindsay, E.A. 2001, Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments. Hum. Mol. Genet., 10, 2645.
57. Kilts, C.D. 2001, The changing roles and targets for animal models of schizophrenia. Biol. Psychiatry, 50, 845.
58. Gogos, J.A., Santha, M., Takacs, Z., Beck, K. D., Luine, V., Lucas, L.R., Nadler, J.V., and Karayiorgou, M. 1999, The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nat. Genet., 21, 434.
59. Cohen, S.M., and Nadler, J.V. 1997, Proline-induced potentiation of glutamate transmission. Brain Res., 761, 271.
60. Goodman, B.K., Rutberg, J., Lin, W.W., Pulver, A.E., and Thomas, G.H. 2000, Hyperprolinaemia in patients with deletion (22)(q11.2) syndrome. J. Inherit. Metab Dis., 23, 847.
61. Jaeken, J., Goemans, N., Fryns, J.P., Francois, I., and de Zegher, F. 1996, Association of hyperprolinaemia type I and heparin cofactor II deficiency with CATCH 22 syndrome: evidence for a contiguous gene syndrome locating the proline oxidase gene. J. Inherit. Metab Dis., 19, 275.
62. Prader, A., Labhart, A., and Willi, H. 1956, Ein Syndrom vom Adipositas, Kleinwuchs, Kryptorchismus und Oligophrenie nach myotonieartigem Zustand. Schweiz. Med. Wochenschr., 86, 1260.
63. Cassidy, S.B. 1997, Prader-Willi syndrome. J. Med. Genet., 34, 917.
64. Zelweger, H. 1988, Differential Diagnosis in Prader-Willi syndrome. In: Management of the Prader-Willi Syndrome, L. R. Greenwag, and R. C. Alexander (Eds.), Springer Verlag, Berlin, 15.
65. Butler, M.G., Meaney, F.J., and Palmer, C.G. 1986, Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. Am. J. Med. Genet., 23, 793.
66. O'Brien, G., and Yule, W. 1994, Behavioral Phenotypes, McKeith Press/Cambridge University Press, London.
67. Clarke, D.J., Boer, H., Chung, M.C., Sturmey, P., and Webb, T. 1996, Maladaptive behaviour in Prader-Willi syndrome in adult life. J. Intellect. Disabil. Res., 40 ( Pt 2), 159.
68. Dykens, E.M., and Kasari, C. 1997, Maladaptive behavior in children with Prader-Willi syndrome, Down syndrome, and nonspecific mental retardation. Am. J. Ment. Retard., 102, 228.
69. Evenhuis, H.M. 1999, Lichamelijke comorbiditeit bij volwassenen met het Prader-Willi syndroom. In: Syndromen en Verstandelijke Handicap: Angelman, Prader-Willi en Nett, L.A.E.M. Loan, and O.F. Brouwer (Eds.), Boerhaave Commissie voor Postacademisch Onderwijs in de Geneeskunde, Leids Universitair Medisch Centrum, Leiden, The Netherlands, 19.
70. Clarke, D., Boer, H., Webb, T., Scott, P., Frazer, S., Vogels, A., Borghgraef, M., and Curfs, L.M. 1998, Prader-Willi syndrome and psychotic symptoms: 1. Case descriptions and genetic studies. J. Intellect. Disabil. Res., 42 ( Pt 6), 440.
71. Verhoeven, W.M., Curfs, L.M., and Tuinier, S. 1998, Prader-Willi syndrome and cycloid psychoses. J. Intellect. Disabil. Res., 42 ( Pt 6), 455.
72. Clarke, D.J. 1993, Prader-Willi syndrome and psychoses. Br. J. Psychiatry, 163, 680.
73. Swaab, D.F. 1997, Prader-Willi syndrome and the hypothalamus. Acta Paediatr. Suppl, 423, 50.
74. Laan, L.A., Haeringen, A., and Brouwer, O.F. 1999, Angelman syndrome: a review of clinical and genetic aspects. Clin. Neurol. Neurosurg., 101, 161.
75. Mann, M.R., and Bartolomei, M.S. 1999, Towards a molecular understanding of Prader-Willi and Angelman syndromes. Hum. Mol. Genet., 8, 1867.
76. Kishono, T., Lalande, M., and Wagstaff, J. 1997, VBE3A/EG-AP mutations cause Angelman syndrome. Nat. Genet., 15, 70.
77. Matsuura, T., Sutcliffe, J.S., Fang, P., Galjaard, R.J., Jiang, Y.H., Benton, C.S., Rommens, J.M., and Beaudet, A.L. 1997, De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat. Genet., 15, 74.
78. Cassidy, S.B., Lai, L.W., Erickson, R.P., Magnuson, L., Thomas, E., Gendron, R., and Herrmann, J. 1992, Trisomy 15 with loss of the paternal 15 as a cause of Prader-Willi syndrome due to maternal disomy. Am. J. Hum. Genet., 51, 701.
79. Purvis-Smith, S.G., Saville, T., Manass, S., Yip, M.Y., Lam-Po-Tang, P.R., Duffy, B., Johnston, H., Leigh, D., and McDonald, B. 1992, Uniparental disomy 15 resulting from "correction" of an initial trisomy 15. Am. J. Hum. Genet., 50, 1348.
80. Roberts, E., Stevenson, K., Cole, T., Redford, D.H., and Davison, E.V. 1997, Prospective prenatal diagnosis of Prader-Willi syndrome due to maternal disomy for chromosome 15 following trisomic zygote rescue. Prenat. Diagn., 17, 780.
81. Shemer, R., Hershko, A.Y., Perk, J., Mostoslavsky, R., Tsuberi, B., Cedar, H., Buiting, K., and Razin, A. 2000, The imprinting box of the Prader-Willi/Angelman syndrome domain. Nat. Genet., 26, 440.
82. Buiting, K., Lich, C., Cootrell, S., Barnicoat, A., and Horsthemke, B. 1999, A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp. Hum. Genet., 105, 665.
83. Barlow, D.P. 1997, Competition--a common motif for the imprinting mechanism? EMBO J., 16, 6899.
84. Ohta, T., Gray, T. A., Rogan, P.K., Buiting, K., Gabriel, J.M., Saitoh, S., Muralidhar, B., Bilienska, B., Krajewska-Walasek, M., Driscoll, D.J., Horsthemke, B., Butler, M.G., and Nicholls, R.D. 1999, Imprinting-mutation mechanisms in Prader-Willi syndrome. Am. J. Hum. Genet., 64, 397.
85. Bressler, J., Tsai, T.F., Wu, M.Y., Tsai, S.F., Ramirez, M.A., Armstrong, D., and Beaudet, A.L. 2001, The SNRPN promoter is not required for genomic imprinting of the Prader- Willi/Angelman domain in mice. Nat. Genet., 28, 232.
86. Buiting, K., Farber, C., Kroisel, P., Wagner, K., Brueton, L., Robertson, M. ., Lich, C., and Horsthemke, B. 2000, Imprinting centre deletions in two PWS families: implications for diagnostic testing and genetic counseling. Clin. Genet., 58, 284.
87. Buiting, K., Barnicoat, A., Lich, C., Pembrey, M., Malcolm, S., and Horsthemke, B. 2001, Disruption of the bipartite imprinting center in a family with Angelman syndrome. Am. J. Hum. Genet., 68, 1290.
88. Watson, P., Black, G., Ramsden, S., Barrow, M., Super, M., Kerr, B., and Clayton-Smith, J. 2001, Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J. Med. Genet., 38, 224.
89. Christian, S.L., Robinson, W.P., Huang, B., Mutirangura, A., Line, M.R., Nakao, M., Surti, U., Chakravarti, A., and Ledbetter, D.H. 1995, Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients. Am. J. Hum. Genet., 57, 40.
90. Knoll, J.H., Nicholls, R.D., Magenis, R.E., Glatt, K., Graham, J.M., Jr., Kaplan, L., and Lalande, M. 1990, Angelman syndrome: three molecular classes identified with chromosome 15q11q13-specific DNA markers. Am. J. Hum. Genet., 47, 149.
91. Kuwano, A., Mutirangura, A., Dittrich, B., Buiting, K., Horsthemke, B., Saitoh, S., Niikawa, N., Ledbetter, S.A., Greenberg, F., and Chinault, A.C. 1992, Molecular dissection of the Prader-Willi/Angelman syndrome region (15q11-13) by YAC cloning and FISH analysis. Hum. Mol. Genet., 1, 417.
92. Amos-Landgraf, J.M., Ji,Y., Gottlieb, W., Depinet, T., Wandstrat, A.E., Cassidy, S.B., Driscoll, D.J., Rogan, P.K., Schwartz, S., and Nicholls, R.D. 1999, Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am. J. Hum. Genet., 65, 370.
93. Buiting, K., Gross, S., Ji, Y., Senger, G., Nicholls, R.D., and Horsthemke, B. 1998, Expressed copies of the MN7 (D15F37) gene family map close to the common deletion breakpoints in the Prader-Willi/Angelman syndromes. Cytogenet. Cell Genet., 81, 247.
94. Ji, Y., Walkowicz, M.J., Buiting, K., Johnson, D.K., Tarvin, R.E., Rinchik, E.M., Horsthemke, B., Stubbs, L., and Nicholls, R.D. 1999, The ancestral gene for transcribed, low-copy repeats in the Prader- Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities. Hum. Mol. Genet., 8, 533.
95. Carrozzo, R., Rossi, E., Christian, S.L., Kittikamron, K., Livieri, C., Corrias, A., Pucci, L., Fois, A., Simi, P., Bosio, L., Beccaria, L., Zuffardi, O., and Ledbetter, D.H. 1997, Inter and Intrachromosomal rearrangements are both involved in the origin of 15q11-13 deletions in Prader-Willi syndrome. Am. J. Hum. Genet., 61, 228.
96. Robinson, W.P., Dutly, F., Nicholls, R.D., Bernasconi, F., Penaherrera, M., Michaelis, R.C., Abeliovich, D., and Schinzel, A.A. 1998, The mechanisms involved in formation of deletions and duplications of 15q11-q13. J. Med. Genet., 35, 130.
97. Christian, S.L., Bhatt, N.K., Martin, S.A., Sutcliffe, J.S., Kubota, T., Huang, B., Mutirangura, A., Chinault, A.C., Beaudet, A.L., and Ledbetter, D.H. 1998, Integrated YAC contig map of the Prader-Willi/Angelman region on chromosome 15q11-q13 with average STS spacing of 35 kb. Genome Res., 8, 146.
98. Muscatelli, F., Abrous, D.N., Massacrier, A., Boccaccio, I., Le Moal, M., Cau, P., and Cremer, H. 2000, Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum. Mol. Genet., 9, 3101.
99. MacDonald, H.R., and Wevrick, R. 1997, The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse. Hum. Mol. Genet., 6, 1873.
100. Wirth, J., Back, E., Huttenhofer, A., Nothwang, H.G., Lich, C., Gross, S., Menzel, C., Schinzel, A., Kioschis, P., Tommerup, N., Ropers, H. H., Horsthemke, B., and Buiting, K. 2001, A translocation breakpoint cluster disrupts the newly defined 3' end of the SNURF-SNRPN transcription unit on chromosome 15. Hum. Mol. Genet., 10, 201.
101. Bartolomei, M.S., and Tilghman, S. M. 1997, Genomic imprinting in mammals. Annu. Rev. Genet., 31, 493.
102. Fang, P., Lev-Lehman, E., Tsai, T.F., Matsuura, T., Benton, C. S., Sutcliffe, J.S., Christian, S.L., Kubota, T., Halley, D.J., Meijers-Heijboer, H., Langlois, S., Graham, J. M. Jr., Beuten, J., Willems, P.J., Ledbetter, D.H., and Beaudet, A.L. 1999, The spectrum of mutations in UBE3A causing Angelman syndrome. Hum. Mol. Genet., 8, 129.
103. Malzac, P., Webber, H., Moncla, A., Graham, J.M., Kukolich, M., Williams, C., Pagon, R.A., Ramsdell, L.A., Kishino, T., and Wagstaff, J. 1998, Mutation analysis of UBE3A in Angelman syndrome patients. Am. J. Hum. Genet., 62, 1353.
104. Rougeulle, C., Glatt, H., and Lalande, M. 1997, The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat. Genet., 17, 14.
105. Jiang, Y.H., Armstrong, D., Albrecht, U., Atkins, C.M., Noebels, J.L., Eichele, G., Sweatt, J.D., and Beaudet, A.L. 1998, Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron, 21, 799.
106. Vu, T.H., and Hoffman, A.R. 1997, Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat. Genet., 17, 12.
107. Sheffner, M., Nuber, U., and Huibregtse, J. M. 1995, Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature, 373, 81.
108. Hamabe, J., Kuroki, Y., Imaizumi, K., Sugimoto, T., Fukushima, Y., Yamaguchi, A., Izumikawa, Y., and Niikawa, N. 1991, DNA deletion and its parental origin in Angelman syndrome patients. Am. J. Med. Genet., 41, 64.
109. Jiang, Y., Lev-Lehman, E., Bressler, J., Tsai, T.F., and Beaudet, A.L. 1999, Genetics of Angelman syndrome. Am. J. Hum. Genet., 65, 1.
110. Meguro, M., Kashiwagi, A., Mitsuya, K., Nakao, M., Kondo, I., Saitoh, S., and Oshimura, M. 2001, A novel maternally expressed gene, ATP10C, encodes a putative aminophospholipid translocase associated with Angelman syndrome. Nat. Genet., 28, 19.
111. Cattanach, B.M., Barr, J.A., Beechey, C.V., Martin, J., Noebels, J., and Jones, J. 1997, A candidate model for Angelman syndrome in the mouse. Mamm. Genome, 8, 472.
112. DeLorey, T.M., Handforth, A., Anagnostaras, S.G., Homanics, G.E., Minassian, B.A., Asatourian, A., Fanselow, M.S., Delgado-Escueta, A., Ellison, G.D., and Olsen, R.W. 1998, Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J. Neurosci., 18, 8505.
113. Cattanach, B.M., Barr, J.A., Evans, E. P., Burtenshaw, M., Beechey, C.V., Leff, S.E., Brannan, C.I., Copeland, N.G., Jenkins, N. A., and Jones, J. 1992, A candidate mouse model for Prader-Willi syndrome which shows an absence of Snrpn expression. Nat. Genet., 2, 270.
114. Gabriel, J.M., Merchant, M., Ohta, T., Ji, Y., Caldwell, R.G., Ramsey, M.J., Tucker, J.D., Longnecker, R., and Nicholls, R.D. 1999, A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and angelman syndromes. Proc. Natl. Acad. Sci. U. S. A, 96, 9258.
115. Tsai, T.F., Jiang, Y.H., Bressler, J., Armstrong, D., and Beaudet, A.L. 1999, Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth retardation and partial lethality and provides evidence for a gene contributing to Prader-Willi syndrome. Hum. Mol. Genet., 8, 1357.
116. Yang, T., Adamson, T.E., Resnick, J.L., Leff, S., Wevrick, R., Francke, U., Jenkins, N.A., Copeland, N.G., and Brannan, C.I. 1998, A mouse model for Prader-Willi syndrome imprinting-centre mutations. Nat. Genet., 19, 25.
117. Gerard, M., Hernandez, L., Wevrick, R., and Stewart, C.L. 1999, Disruption of the mouse necdin gene results in early post-natal lethality. Nat. Genet., 23, 199.
118. Lee, S., Kozlov, S., Hernandez, L., Chamberlain, S.J., Brannan, C.I., Stewart, C. L., and Wevrick, R. 2000, Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the homologous murine imprinting phenotype. Hum. Mol. Genet., 9, 1813.
119. Smith, A., Wiles, C., Haan, E., McGill, J., Wallace, G., Dixon, J., Selby, R., Colley, A., Marks, R., and Trent, R.J. 1996, Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion. J. Med. Genet., 33, 107.
120. Smith, A., Marks, R., Haan, E., Dixon, J., and Trent, R.J. 1997, Clinical features in four patients with Angelman syndrome resulting from paternal uniparental disomy. J. Med. Genet., 34, 426.
121. Smith, A.C., Dykens, E., and Greenberg, F. 1998, Behavioral phenotype of Smith-Magenis syndrome (del 17p11.2). Am. J. Med. Genet., 81, 179.
122. Minassian, B.A., DeLorey, T.M., Olsen, R. W., Philippart, M., Bronstein, Y., Zhang, Q., Guerrini, R., Van Ness, P., Livet, M.O., and Delgado-Escueta, A.V. 1998, Angelman syndrome: correlations between epilepsy phenotypes and genotypes. Ann. Neurol., 43, 485.
123. Cassidy, S.B., Dykens, E., and Williams, C. A. 2000, Prader-Willi and Angelman syndromes: sister imprinted disorders. Am. J. Med. Genet., 97, 136.
124. Boer, H., Holland, A., Whittington, J., Butler, J., Webb, T., and Clarke, D. 2002, Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet, 359, 135.
125. Harvey, J. 1998, Draft Best Practice Guidelines for Molecular Analysis of Prader-Willi and Angelman Syndromes.Guidelines prepared by John Harvey for the UK Clinical Molecular Genetics Society (CMGS). Updated August 1998.
126. Kubota, T., Das, S., Christian, S.L., Baylin, S. B., Herman, J.G., and Ledbetter, D.H. 1997, Methylation-specific PCR simplifies imprinting analysis. Nat. Genet., 16, 16.
127. Zeschnigk, M., Lich, C., Buiting, K., Doerfler, W., and Horsthemke, B. 1997, A single-tube PCR test for the diagnosis of Angelman and Prader-Willi syndrome based on allelic methylation differences at the SNRPN locus. Eur. J. Hum. Genet., 5, 94.
128. Riccardi, V.M. 1991, Neurofibromatosis: past, present, and future. N. Engl. J. Med., 324, 1283.
129. Wallace, M.R., Marchuk, D.A., Andersen, L.B., Letcher, R., Odeh, H.M., Saulino, A. M., Fountain, J.W., Brereton, A., Nicholson, J., and Mitchell, A.L. 1990, Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science, 249, 181.
130. Rouleau, G.A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, S., Desmaze, C., and Plougastel, B. 1993, Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature, 363, 515.
131. Huson, S.M., Compston, D.A., and Harper, P. S. 1989, A genetic study of von Recklinghausen neurofibromatosis in south east Wales. II. Guidelines for genetic counselling. J. Med. Genet., 26, 712.
132. Dugoff, L., and Sujansky, E. 1996, Neurofibromatosis type 1 and pregnancy. Am. J. Med. Genet., 66, 7.
133. Korf, B.R. 1999, Plexiform neurofibromas. Am. J. Med. Genet., 89, 31.
134. Hochstrasser, H., Boltshauser, E., and Valavanis, A. 1988, Brain tumors in children with von Recklinghausen neurofibromatosis. Neurofibromatosis., 1, 233.
135. Habiby, R., Silverman, B., Listernick, R., and Charrow, J. 1997, Neurofibromatosis type I and precocious puberty: beyond the chasm. J. Pediatr., 131, 786.
136. Listernick, R., Charrow, J., and Gutmann, D.H. 1999, Intracranial gliomas in neurofibromatosis type 1. Am. J. Med. Genet., 89, 38.
137. Hope, D.G., and Mulvihill, J.J. 1981, Malignancy in neurofibromatosis. Adv. Neurol., 29, 33.
138. Riccardi, V.M., Womack, J.E., and Jacks, T. 1994, Neurofibromatosis and related tumors. Natural occurrence and animal models. Am. J. Pathol., 145, 994.
139. Matsui, I., Tanimura, M., Kobayashi, N., Sawada, T., Nagahara, N., and Akatsuka, J. 1993, Neurofibromatosis type 1 and childhood cancer. Cancer, 72, 2746.
140. Emanuel, P.D. 1999, Myelodysplasia and myeloproliferative disorders in childhood: an update. Br. J. Haematol., 105, 852.
141. Duffner, P.K., Cohen, M.E., Seidel, F.G., and Shucard, D.W. 1989, The significance of MRI abnormalities in children with neurofibromatosis. Neurology, 39, 373.
142. Janss, A.J., Grundy, R., Cnaan, A., Savino, P.J., Packer, R.J., Zackai, E.H., Goldwein, J.W., Sutton, L.N., Radcliffe, J., and Molloy, P.T. 1995, Optic pathway and hypothalamic/chiasmatic gliomas in children younger than age 5 years with a 6-year follow-up. Cancer, 75, 1051.
143. Sevick, R.J., Barkovich, A.J., Edwards, M.S., Koch, T., Berg, B., and Lempert, T. 1992, Evolution of white matter lesions in neurofibromatosis type 1: MR findings. AJR Am. J. Roentgenol., 159, 171.
144. Bawden, H., Dooley, J., Buckley, D., Camfield, P., Gordon, K., Riding, M., and Llewellyn, G. 1996, MRI and nonverbal cognitive deficits in children with neurofibromatosis 1. J. Clin. Exp. Neuropsychol., 18, 784.
145. Joy, P., Roberts, C., North, K., and de Silva, M. 1995, Neuropsychological function and MRI abnormalities in neurofibromatosis type 1. Dev. Med. Child Neurol., 37, 906.
146. Moore, B.D., Slopis, J.M., Schomer, D., Jackson, E.F., and Levy, B.M. 1996, Neuropsychological significance of areas of high signal intensity on brain MRIs of children with neurofibromatosis. Neurology, 46, 1660.
147. North, K. 2000, Neurofibromatosis type 1. Am. J. Med. Genet., 97, 119.
148. Ferner, R.E., Chaudhuri, R., Bingham, J., Cox, T., and Hughes, R.A. 1993, MRI in neurofibromatosis 1. The nature and evolution of increased intensity T2 weighted lesions and their relationship to intellectual impairment. J. Neurol. Neurosurg. Psychiatry, 56, 492.
149. Legius, E., Descheemaeker, M.J., Spaepen, A., Casaer, P., and Fryns, J.P. 1994, Neurofibromatosis type 1 in childhood: a study of the neuropsychological profile in 45 children. Genet. Couns., 5, 51.
150. Heikkinen, E.S., Poyhonen, M.H., Kinnunen, P.K., and Seppanen, U.I. 1999, Congenital pseudarthrosis of the tibia. Treatment and outcome at skeletal maturity in 10 children. Acta Orthop. Scand., 70, 275.
151. Samuelsson, B., and Riccardi, V. M. 1989, Neurofibromatosis in Gothenburg, Sweden. II. Intellectual compromise. Neurofibromatosis., 2, 78.
152. Wadsby, M., Lindehammar, H., and Eeg-Olofsson, O. 1989, Neurofibromatosis in childhood: neuropsychological aspects. Neurofibromatosis., 2, 251.
153. Ozonoff, S. 1999, Cognitive impairment in neurofibromatosis type 1. Am. J. Med. Genet., 89, 45.
154. North, K.N., Riccardi, V., Samango-Sprouse, C., Ferner, R., Moore, B., Legius, E., Ratner, N., and Denckla, M.B. 1997, Cognitive function and academic performance in neurofibromatosis. 1: consensus statement from the NF1 Cognitive Disorders Task Force. Neurology, 48, 1121.
155. Koth, C.W., Cutting, L.E., and Denckla, M.B. 2000, The association of neurofibromatosis type 1 and attention deficit hyperactivity disorder. Neuropsychol. Dev. Cogn Sect. C. Child Neuropsychol., 6, 185.
156. Johnson, N.S., Saal, H.M., Lovell, A.M., and Schorry, E.K. 1999, Social and emotional problems in children with neurofibromatosis type 1: evidence and proposed interventions. J. Pediatr., 134, 767.
157. Zoller, M.E., and Rembeck, B. 1999, A psychiatric 12-year follow-up of adult patients with neurofibromatosis type 1. J. Psychiatr. Res., 33, 63.
158. Upadhyaya, M., Ruggieri, M., Maynard, J., Osborn, M., Hartog, C., Mudd, S., Penttinen, M., Cordeiro, I., Ponder, M., Ponder, B.A., Krawczak, M., and Cooper, D.N. 1998, Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum. Genet., 102, 591.
159. Lopez-Correa, C. 2001, Molecular and Clinical Characterisation of NF1 Gene Microdeletions., Thesis. Leuven University Press.
160. Lopez-Correa, C., Brems, H., Lazaro, C., Marynen, P., and Legius, E. 2000, Unequal meiotic crossover: a frequent cause of NF1 microdeletions. Am. J. Hum. Genet., 66, 1969.
161. Dorschner, M. O., Sybert, V.P., Weaver, M., Pletcher, B.A., and Stephens, K. 2000, NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. Hum. Mol. Genet., 9, 35.
162. Jenne, D.E., Tinschert, S., Reimann, H., Lasinger, W., Thiel, G., Hameister, H., and Kehrer-Sawatzki, H. 2001, Molecular characterization and gene content of breakpoint boundaries in patients with neurofibromatosis type 1 with 17q11.2 microdeletions. Am. J. Hum. Genet., 69, 516.
163. Cawthon, R.M., Weiss, R., Xu, G.F., Viskochil, D., Culver, M., Stevens, J., Robertson, M., Dunn, D., Gesteland, R., and O'Connell, P. 1990, A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell, 62, 193.
164. Gutmann, D.H., Wood, D.L., and Collins, F.S. 1991, Identification of the neurofibromatosis type 1 gene product. Proc. Natl. Acad. Sci. U. S. A, 88, 9658.
165. Shannon, K.M., O'Connell, P., Martin, G.A., Paderanga, D., Olson, K., Dinndorf, P., and McCormick, F. 1994, Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N. Engl. J. Med., 330, 597.
166. Colman, S.D., Williams, C.A., and Wallace, M.R. 1995, Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Nat. Genet., 11, 90.
167. The, I., Murthy, A.E., Hannigan, G.E., Jacoby, L.B., Menon, A.G., Gusella, J.F., and Bernards, A. 1993, Neurofibromatosis type 1 gene mutations in neuroblastoma. Nat. Genet., 3, 62.
168. Johnson, M.R., Look, A.T., DeClue, J. E., Valentine, M.B., and Lowy, D.R. 1993, nactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras. Proc. Natl. Acad. Sci. U. S. A, 90, 5539.
169. Marchuk, D.A., Saulino, A. M., Tavakkol, R., Swaroop, M., Wallace, M.R., Andersen, L.B., Mitchell, A.L., Gutmann, D.H., Boguski, M., and Collins, F.S. 1991, cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics, 11, 931.
170. Izawa, I., Tamaki, N., and Saya, H. 1996, Phosphorylation of neurofibromatosis type 1 gene product (neurofibromin) by cAMP-dependent protein kinase. FEBS Lett., 382, 53.
171. Guo, H.F., The, I., Hannan, F., Bernards, A., and Zhong, Y. 1997, Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science, 276, 795.
172. The, I., Hannigan, G.E., Cowley, G.S., Reginald, S., Zhong, Y., Gusella, J. F., Hariharan, I.K., and Bernards, A. 1997, Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. Science, 276, 791.
173. Andersen, L.B., Fountain, J.W., Gutmann, D.H., Tarle, S.A., Glover, T.W., Dracopoli, N.C., Housman, D.E., and Collins, F.S. 1993, Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines. Nat. Genet., 3, 118.
174. Ducatman, B.S., Scheithauer, B.W., Piepgras, D.G., Reiman, H.M., and Ilstrup, D. M. 1986, Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer, 57, 2006.
175. Cichowski, K., Shih, T.S., Schmitt, E., Santiago, S., Reilly, K., McLaughlin, M.E., Bronson, R.T., and Jacks, T. 1999, Mouse models of tumor development in neurofibromatosis type 1. Science, 286, 2172.
176. Vogel, K.S., and Parada, L.F. 1998, Sympathetic neuron survival and proliferation are prolonged by loss of p53 and neurofibromin. Mol. Cell Neurosci., 11, 19.
177. Danglot, G., Regnier, V., Fauvet, D., Vassal, G., Kujas, M., and Bernheim, A. 1995, Neurofibromatosis 1 (NF1) mRNAs expressed in the central nervous system are differentially spliced in the 5' part of the gene. Hum. Mol. Genet., 4, 915.
178. Geist, R.T., and Gutmann, D.H. 1996, Expression of a developmentally-regulated neuron-specific isoform of the neurofibromatosis 1 (NF1) gene. Neurosci. Lett., 211, 85.
179. Silva, A.J., Frankland, P.W., Marowitz, Z., Friedman, E., Lazlo, G., Cioffi, D., Jacks, T., and Bourtchuladze, R. 1997, A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat. Genet., 15, 281.
180. Brannan, C.I., Perkins, A.S., Vogel, K.S., Ratner, N., Nordlund, M.L., Reid, S.W., Buchberg, A.M., Jenkins, N.A., Parada, L.F., and Copeland, N.G. 1994, Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev., 8, 1019.
181. Jacks, T., Shih, T.S., Schmitt, E.M., Bronson, R.T., Bernards, A., and Weinberg, R.A. 1994, Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat. Genet., 7, 353.
182. Gutmann, D.H., Loehr, A., Zhang, Y., Kim, J., Henkemeyer, M., and Cashen, A. 1999, Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation. Oncogene, 18, 4450.
183. Rutkowski, J.L., Wu, K., Gutmann, D.H., Boyer, P.J., and Legius, E. 2000, Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1. Hum. Mol. Genet., 9, 1059.
184. Serra, E., Rosenbaum, T., Winner, U., Aledo, R., Ars, E., Estivill, X., Lenard, H.G., and Lazaro, C. 2000, Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Hum. Mol. Genet., 9, 3055.
185. Ainsworth, P.J., Chakraborty, P.K., and Weksberg, R. 1997, Example of somatic mosaicism in a series of de novo neurofibromatosis type 1 cases due to a maternally derived deletion. Hum. Mutat., 9, 452.
186. Lazaro, C., Gaona, A., Ainsworth, P., Tenconi, R., Vidaud, D., Kruyer, H., Ars, E., Volpini, V., and Estivill, X. 1996, Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients. Hum. Genet., 98, 696.
187. van Asperen, C.J., Overweg-Plandsoen, W.C., Cnossen, M.H., van Tijn, D.A., and Hennekam, R.C. 1998, Familial neurofibromatosis type 1 associated with an overgrowth syndrome resembling Weaver syndrome. J. Med. Genet., 35, 323.
188. Wu, R., Lopez-Correa, C., Rutkowski, J.L., Baumbach, L.L., Glover, T.W., and Legius, E. 1999, Germline mutations in NF1 patients with malignancies. Genes Chromosomes Cancer, 26, 376.
189. Serra, E., Puig, S., Otero, D., Gaona, A., Kruyer, H., Ars, E., Estivill, X., and Lazaro, C. 1997, Confirmation of a double-hit model for the NF1 gene in benign neurofibromas. Am. J. Hum. Genet., 61, 512.
190. Karmiloff-Smith, A., Tyler, L.K., Voice, K., Sims, K., Udwin, O., Howlin, P., and Davies, M. 1998, Linguistic dissociations in Williams syndrome: evaluating receptive syntax in on-line and off-line tasks. Neuropsychologia, 36, 343.
191. Reiss, A.L., Eliez, S., Schmitt, J.E., Straus, E., Lai, Z., Jones, W., and Bellugi, U. 2000, IV. Neuroanatomy of Williams syndrome: a high-resolution MRI study. J. Cogn Neurosci., 12 Suppl 1, 65.
192. Dutly, F., and Schinzel, A. 1996, Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome. Hum. Mol. Genet., 5, 1893.
193. Osborne, L.R., Herbrick, J.A., Greavette, T., Heng, H.H., Tsui, L.C., and Scherer, S.W. 1997, PMS2-related genes flank the rearrangement breakpoints associated with Williams syndrome and other diseases on human chromosome 7. Genomics, 45, 402.
194. Robinson, W.P., Waslynka, J., Bernasconi, F., Wang, M., Clark, S., Kotzot, D., and Schinzel, A. 1996, Delineation of 7q11.2 deletions associated with Williams-Beuren syndrome and mapping of a repetitive sequence to within and to either side of the common deletion. Genomics, 34, 17.
195. Ewart, A.K., Morris, C.A., Atkinson, D., Jin, W., Sternes, K., Spallone, P., Stock, A.D., Leppert, M., and Keating, M.T. 1993, Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat. Genet., 5, 11.
196. Francke, U. 1999, Williams-Beuren syndrome: genes and mechanisms. Hum. Mol. Genet., 8, 1947.
197. Hockenhull, E.L., Carette, M.J., Metcalfe, K., Donnai, D., Read, A.P., and Tassabehji, M. 1999, A complete physical contig and partial transcript map of the Williams syndrome critical region. Genomics, 58, 138.
198. Osborne, L.R. 1999, Williams-Beuren syndrome: unraveling the mysteries of a microdeletion disorder. Mol. Genet. Metab, 67, 1.
199. Perez Jurado, L.A., Peoples, R., Kaplan, P., Hamel, B.C., and Francke, U. 1996, Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth. Am. J. Hum. Genet., 59, 781.
200. Hoogenraad, C.C., Eussen, B.H., Langeveld, A., van Haperen, R., Winterberg, S., Wouters, C.H., Grosveld, F., De Zeeuw, C.I., and Galjart, N. 1998, The murine CYLN2 gene: genomic organization, chromosome localization, and comparison to the human gene that is located within the 7q11.23 Williams syndrome critical region. Genomics, 53, 348.
201. Osborne, L.R., Soder, S., Shi, X.M., Pober, B., Costa, T., Scherer, S.W., and Tsui, L.C. 1997, Hemizygous deletion of the syntaxin 1A gene in individuals with Williams syndrome. Am. J. Hum. Genet., 61, 449.
202. Botta, A., Novelli, G., Mari, A., Novelli, A., Sabani, M., Korenberg, J., Osborne, L. R., Digilio, M.C., Giannotti, A., and Dallapiccola, B. 1999, Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes. J. Med. Genet., 36, 478.
203. Frangiskakis, J.M., Ewart, A.K., Morris, C. A., Mervis, C.B., Bertrand, J., Robinson, B.F., Klein, B.P., Ensing, G.J., Everett, L.A., Green, E.D., Proschel, C., Gutowski, N.J., Noble, M., Atkinson, D.L., Odelberg, S.J., and Keating, M.T. 1996, LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell, 86, 59.
204. Tassabehji, M., Metcalfe, K., Karmiloff-Smith, A., Carette, M. ., Grant, J., Dennis, N., Reardon, W., Splitt, M., Read, A.P., and Donnai, D. 1999, Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. Am. J. Hum. Genet., 64, 118.
205. DeSilva, U., Massa, H., Trask, B.J., and Green, E.D. 1999, Comparative mapping of the region of human chromosome 7 deleted in williams syndrome. Genome Res., 9, 428.
206. Doyle, J. L., DeSilva, U., Miller, W., and Green, E.D. 2000, Divergent human and mouse orthologs of a novel gene (WBSCR15/Wbscr15) reside within the genomic interval commonly deleted in Williams syndrome. Cytogenet. Cell Genet., 90, 285.
207. Willekens, D., De Cock, P., and Fryns, J.P. 2000, Three young children with Smith-Magenis syndrome: their distinct, recognisable behavioural phenotype as the most important clinical symptoms. Genet. Couns., 11, 103.
208. Dykens, E.M., and Smith, A.C. 1998, Distinctiveness and correlates of maladaptive behaviour in children and adolescents with Smith-Magenis syndrome. J. Intellect. Disabil. Res., 42 ( Pt 6), 481.
209. Greenberg, F., Guzzetta, V., Montes de Oca-Luna, R., Magenis, R. E., Smith, A.C., Richter, S.F., Kondo, I., Dobyns, W.B., Patel, P.I., and Lupski, J.R. 1991, Molecular analysis of the Smith-Magenis syndrome: a possible contiguous- gene syndrome associated with del(17)(p11.2). Am. J. Hum. Genet., 49, 1207.
210. Finucane, B.M., Konar, D., Haas-Givler, B., Kurtz, M.B., and Scott, C.I. Jr. 1994, The spasmodic upper-body squeeze: a characteristic behavior in Smith- Magenis syndrome. Dev. Med. Child Neurol., 36, 78.
211. Smith, A.C., Dykens, E., and Greenberg, F. 1998, Sleep disturbance in Smith-Magenis syndrome (del 17 p11.2). Am. J. Med. Genet., 81, 186.
212. Park, J.P., Moeschler, J. B., Davies, W.S., Patel, P.I., and Mohandas, T.K. 1998, Smith-Magenis syndrome resulting from a de novo direct insertion of proximal 17q into 17p11.2. Am. J. Med. Genet., 77, 23.
213. Smith, A.C., McGavran, L., Robinson, J., Waldstein, G., Macfarlane, J., Zonona, J., Reiss, J., Lahr, M., Allen, L., and Magenis, E. 1986, Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am. J. Med. Genet., 24, 393.
214. De Leersnyder, H., de Blois, M.C., Claustrat, B., Romana, S., Albrecht, U., Kleist-Retzow, J.C., Delobel, B., Viot, G., Lyonnet, S., Vekemans, M., and Munnich, A. 2001, Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome. J. Pediatr., 139, 111.
215. Potocki, L., Chen, K.S., Park, S.S., Osterholm, D.E., Withers, M.A., Kimonis, V., Summers, A.M., Meschino, W.S., Anyane-Yeboa, K., Kashork, C.D., Shaffer, L.G., and Lupski, J.R. 2000, Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat. Genet., 24, 84.
216. Chen, K.S., Manian, P., Koeuth, T., Potocki, L., Zhao, Q., Chinault, A.C., Lee, C.C., and Lupski, J.R. 1997, Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat. Genet., 17, 154.
217. Seranski, P., Heiss, N.S., Dhorne-Pollet, S., Radelof, U., Korn, B., Hennig, S., Backes, E., Schmidt, S., Wiemann, S., Schwarz, C.E., Lehrach, H., and Poustka, A. 1999, Transcription mapping in a medulloblastoma breakpoint interval and Smith-Magenis syndrome candidate region: identification of 53 transcriptional units and new candidate genes. Genomics, 56, 1.
218. Seranski, P., Hoff, C., Radelof, U., Hennig, S., Reinhardt, R., Schwartz, C.E., Heiss, N. S., and Poustka, A. 2001, RAI1 is a novel polyglutamine encoding gene that is deleted in Smith- Magenis syndrome patients. Gene, 270, 69.
219. Potocki, L., Glaze, D., Tan, D.X., Park, S.S., Kashork, C.D., Shaffer, L.G., Reiter, R.J., and Lupski, J.R. 2000, Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. J. Med. Genet., 37, 428.
220. Probst, F.J., Chen, K.S., Zhao, Q., Wang, A., Friedman, T. B., Lupski, J. R., and Camper, S. A. 1999, A physical map of the mouse shaker-2 region contains many of the genes commonly deleted in Smith-Magenis syndrome (del17p11.2p11.2). Genomics, 55, 348.
221. Digilio, M.C., Marino, B., Guccione, P., Giannotti, A., Mingarelli, R., and Dallapiccola, B. 1998, Deletion 8p syndrome. Am. J. Med. Genet., 75, 534.
222. Marino, B., Reale, A., Giannotti, A., Digilio, M.C., and Dallapiccola, B. 1992, Nonrandom association of atrioventricular canal and del (8p) syndrome. Am. J. Med. Genet., 42, 424.
223. Claeys, I., Holvoet, M., Eyskens, B., Adriaensens, P., Gewillig, M., Fryns, J.P., and Devriendt, K. 1997, A recognisable behavioural phenotype associated with terminal deletions of the short arm of chromosome 8. Am. J. Med. Genet., 74, 515.
224. Giglio, S., Broman, K.W., Matsumoto, N., Calvari, V., Gimelli, G., Neumann, T., Ohashi, H., Voullaire, L., Larizza, D., Giorda, R., Weber, J.L., Ledbetter, D.H., and Zuffardi, O. 2001, Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am. J. Hum. Genet., 68, 874.
225. Floridia, G., Piantanida, M., Minelli, A., Dellavecchia, C., Bonaglia, C., Rossi, E., Gimelli, G., Croci, G., Franchi, F., Gilgenkrantz, S., Grammatico, P., Dalpra, L., Wood, S., Danesino, C., and Zuffardi, O. 1996, The same molecular mechanism at the maternal meiosis I produces mono- and dicentric 8p duplications. Am. J. Hum. Genet., 58, 785.
226. Devriendt, K., Matthijs, G., Van Dael, R., Gewillig, M., Eyskens, B., Hjalgrim, H., Dolmer, B., McGaughran, J., Brondum-Nielsen, K., Marynen, P., Fryns, J.P., and Vermeesch, J. R. 1999, Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1. Am. J. Hum. Genet., 64, 1119.
227. Neumann, T., Exeler, R., Wittwer, B., Müller-Navia, J., Schrörs, E., Kennerknecht, I., and Horst, J. 1999, A small supernumerary acentric marker chromosome 8 in a 23 year old slightly dysmorphic patient without mental retardaton. Cytogenet. Cell Genet., 85, 158.
228. Pehlivan, T., Pober, B.R., Brueckner, M., Garrett, S., Slaugh, R., Van Rheeden, R., Wilson, D. B., Watson, M.S., and Hing, A. . 1999, GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. Am. J. Med. Genet., 83, 201.
229. de Vries, B.B., Lees, M., Knight, S.J., Regan, R., Corney, D., Flint, J., Barnicoat, A., and Winter, R. M. 2001, Submicroscopic 8pter deletion, mild mental retardation, and behavioral problems caused by a familial t(8;20)(p23;p13). Am. J. Med. Genet., 99, 314.
|Written||2004-02||Annick Vogels, Jean-Pierre Fryns|
|Chairman, Genetics Department CME-UZ, Center for Human Genetics, University Hospital of Leuven, Herestraat, 49 - B-3000 Leuven, Belgium|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Fri Feb 23 20:59:26 CET 2018|
For comments and suggestions or contributions, please contact us