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Microdeletions and Molecular Genetics

By Annick VOGELS and Jean-Pierre FRYNS.

Center for Human, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium





Long version



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 [1]. 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 [2]. However, progress towards the identification of these developmental genes has been slow.

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.




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 [12]. Most deletions are the result of a de novo event, although probably 5-10% are inherited [11]. Several diagnostic labels have been used for this syndrome including Di George syndrome (DGS) [13], Conotruncal anomaly face syndrome or Takao syndrome [14]. Shprintzen syndrome [15] and 22q11deletion syndrome [16].

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 [10] 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 [16]. 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%) [17].

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 [19]. A wide variety of child psychiatric disorders has been reported including attentions deficit disorder and rapidly cycling bipolar disorder in late childhood and adolescence [23], childhood schizophrenia [24,25] and mood disorders [26]. Current estimates are that +/- 35 % of patients develop psychiatric disorders in adolescence or adulthood [27]. 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].


Molecular genetics

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 [11]. 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 [44]. 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 [45] 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].




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 [62]. 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 [63]. The syndrome is now considered as a multistage disorder characterised by three different phases [64].

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 [73].


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 [74]. 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 [75]. 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 [99]. 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 [101]. 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].


Genotype/phenotype correlation

Genotypic / phenotypic correlations with these different genetic causes were identified. Individuals with a deletion show the classic signs of AS [119]. 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 [122]. Further refinement of the phenotype/ genotype correlation will progressively improve the gene-behaviour understanding [123].
A correlation between psychiatric disorders in PWS and uniparental disomy has recently been reported [124]. 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 [128]. 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 [129] and the NF2 gene located on chromosome 22q12.2 [130]. 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 [131]. 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 [132].

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) [139]. 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 [140].

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 [150].

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 [153]. There is no specific characteristic profile of learning disability in NF1 [154]. 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 [155], 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 [156]. 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 [157]. 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 [158] and have a size of 1.5 Mb. Most cases have a de novo deletion [159]. 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) [162]. 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 [159]. 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 [163]. 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 [164]. 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 [187]. 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 [188]. 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 [189]. 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.




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 [190]. 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 [191]. 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.


Molecular Genetics

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 [192]. 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. [9]. 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 [34]. Recently, Osborne et al. [9] 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 [9] 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 [9].


Genes within the deletion

In 1993, Ewart et al demonstrated linkage of isolated familial supravalvular aortastenosis (SVAS) to the elastine gene (ELN) [195]. 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.




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 [121]. The most characteristic features in children include neurobehavioral abnormalities such as aggressive and self-injurious behaviour (SIB) and significant sleep disturbances and stereotypical behaviours [207]. Behaviour problems include disobedience, hyperactivity, tantrums, attention seeking, sleep distortion, lability, property destruction, impulsivity, bed wetting and argumentative behaviour [208]. 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 [209]. With increasing age and ability, the overall prevalence of SIB as well as the number of different types of SIB are increasing [210]. 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 [211]. Stereotypical behaviours are an important clinical symptom in the diagnosis. Many SMS persons show self-hugging, behaviour and spasmodic upper body squeeze [210]. 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.


Molecular genetics

Mechanisms leading to the deletion [7]

Most patients have a 5 Mb common deletion of 17p11.2 [8]. The deletion in the 17p11.2 band in SMS patients occurs between two flanking repeat gene clusters [216].


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 [218].




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 [223].


Molecular genetics

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 [224].

Different rearrangements are associated with the distal 8p region including inv dup(8p) [225], del (8p23.1) [226], small marker chromosome der(8) (p23-pter) [227] and inv(8p). The type of rearrangement is predominantly defined by the orientation of recombining duplicons and the number of crossovers [7].


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. [226]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 [224] 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.




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Written2004-02Annick 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 : Tue Jan 17 17:44:05 CET 2017

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