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.
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 .
he 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].
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 (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 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
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
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
IC defects are found in 2 % of the AS cases and in less than 1 % of the 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.
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
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
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:
(NF 1) and
(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.
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 .
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,
(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
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.
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.
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 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.
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 .
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.
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.
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.
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 .
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 .
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
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.,
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,
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,
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.,
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,
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,
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.,
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. ODonnell, 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,
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. OBrien, 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.,
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.,
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.,
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.,
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,
106. Vu, T.H., and Hoffman, A.R. 1997, Imprinting
of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat. Genet.,
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,
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.,
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,
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,
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.,
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.,
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,
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,
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.,
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.,
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
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.,
163. Cawthon, R.M., Weiss, R., Xu, G.F.,
Viskochil, D., Culver, M., Stevens, J., Robertson, M., Dunn, D., Gesteland,
R., and OConnell, 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., OConnell, 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,
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,
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,
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,
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.,
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
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,
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,
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.,
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.,
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.,
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,
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.
Vogels A, Fryns JP
Atlas of Genetics and Cytogenetics in Oncology and Haematology 2004-02-01
Microdeletions and Molecular Genetics
Online version: http://atlasgeneticsoncology.org/teaching/30059/microdeletions-and-molecular-genetics