Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome.

BACKGROUND: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. METHODS: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region. RESULTS: The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients. CONCLUSIONS: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.

Drayer's syndrome of mental retardation, microcephaly, short stature and absent phalanges is caused by a recurrent deletion of chromosome 15(q26.2-->qter).

We reevaluated a unique family with two sibs who had a presumed autosomal recessively inherited syndrome characterized by mental retardation, microcephaly, short stature and absent phalanges. This family was originally described by Drayer et al. in 1977. Using modern molecular techniques, we demonstrated that the syndrome is caused by the recurrence of an apparently de novo 15qter deletion of 5.8 Mb. Analysis of polymorphic markers revealed that the deletion was of maternal origin in both cases, indicating germline mosaicism in the clinically unaffected mother. This study demonstrates the possibility of parental mosaicism and the risk of recurrence in sibs for terminal subtelomeric deletions.

Growth charts for Wolf-Hirschhorn syndrome (0-4 years of age).

Wolf-Hirschhorn syndrome is characterized by severe growth and mental retardation, microcephaly, seizures and 'Greek helmet' facies, caused by partial deletion of the short arm of chromosome 4. Growth charts are given from 0-4 years of age, based on the study of 101 individuals. Use of these specific growth charts is recommended, because standard growth charts are inapplicable for patients with WHS.

Cytogenetic genotype-phenotype studies: improving genotyping, phenotyping and data storage.

High-resolution molecular cytogenetic techniques such as genomic array CGH and MLPA detect submicroscopic chromosome aberrations in patients with unexplained mental retardation. These techniques rapidly change the practice of cytogenetic testing. Additionally, these techniques may improve genotype-phenotype studies of patients with microscopically visible chromosome aberrations, such as Wolf-Hirschhorn syndrome, 18q deletion syndrome and 1p36 deletion syndrome. In order to make the most of high-resolution karyotyping, a similar accuracy of phenotyping is needed to allow researchers and clinicians to make optimal use of the recent advances. International agreements on phenotype nomenclature and the use of computerized 3D face surface models are examples of such improvements in the practice of phenotyping patients with chromosomal anomalies. The combination of high-resolution cytogenetic techniques, a comprehensive, systematic system for phenotyping and optimal data storage will facilitate advances in genotype-phenotype studies and a further deconstruction of chromosomal syndromes. As a result, critical regions or single genes can be determined to be responsible for specific features and malformations.

European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA); an online database for rare chromosome abnormalities.

During recent years a considerable improvement in diagnostic techniques has enabled cytogeneticists to find more and smaller chromosomal aberrations. However, accurate clinical knowledge about rare chromosome disorders is frequently lacking, mostly due to a significant decline in publishable cases. On the other hand, there is an increasing demand from parents and physicians for reliable information. In order to improve the quality and the quantity of data available, we designed a new database named the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA) at http://www.ecaruca.net. This Internet-database contains cytogenetic and clinical data of patients with rare chromosome abnormalities, including microscopically visible aberrations, as well as microdeletions and -duplications. Cases with certain breakpoints collected in the Zurich Cytogenetic Database were transferred to ECARUCA. The advantages of ECARUCA compared to existing sources are that ECARUCA is interactive, dynamic and has long-term possibilities to store cytogenetic, molecular and clinical data. Professionals can login to submit new cases and perform searches in the database through the Internet. Currently the database contains 1500 unique chromosomal aberrations from almost 4000 patients. A frequent submission of new data ensures the up-to-date quality of the collection. Individual parent accounts allow parents to inform the ECARUCA team about the follow-up of their child. The ECARUCA database provides health care workers with accurate information on clinical aspects of rare chromosome disorders. Additionally, detailed correlations between chromosome aberrations and their phenotypes are of invaluable help in localising genes for mental retardation and congenital anomalies.

Neuroimaging in nine patients with inversion duplication of the short arm of chromosome 8.

Inversion duplication 8p is a rare chromosome disorder characterised by severe mental retardation, minor facial dysmorphisms, and corpus callosum agenesis. Few cerebral imaging studies have been reported. We describe 9 patients with an inversion duplication 8p, involving variable segments of the short arm of chromosome 8. MRI was performed in 8 patients and 2 patients underwent CT scanning. The images were systematically reviewed. All patients suffered from severe mental retardation. Head circumference was between 0 and + 2 SD in 7 patients. The corpus callosum was absent in 6, and thin (but complete) in 3 patients. Hypoplasia of the (inferior) cerebellar vermis was observed in 6 patients. Enlargement of the ventricular system and associated hippocampal maldevelopment were found in all patients. The supratentorial external CSF spaces were enlarged in 6 patients, and in 3 patients there was a remarkable enlargement of the retrocerebellar arachnoidal space. Cerebral white matter showed mildly delayed myelination in 7 patients, and periventricular lesions of variable extent in 6 patients. The pattern of imaging abnormalities was non-specific, but remarkably similar between patients. We found no correlation between the severity of the clinical features, imaging results, and extent of the chromosomal aberration.

Cryptic duplication of the distal segment of 22q due to a translocation (21;22): three case reports and a review of the literature.

Duplications of the proximal segment of chromosome 22q are not uncommon, like Cat-eye syndrome and duplications due to familial (11;22) translocations. However, duplications of the distal long arm of chromosome 22 (22qter) seem to be exceedingly rare. So far, duplications of 22q12 or 22q13 to 22qter have been described in 21 patients, of whom 13 had a pure duplication 22qter. Here we report on three new cases with a pure duplication of the distal part of 22q. The first patient carries a duplication of terminal 22q due to a de novo unbalanced translocation, 46,XX,der(21)t(21;22) (p13;q13.2), detected by NOR-staining, while the other patients have a familial cryptic duplication of terminal 22q due to an unbalanced translocation, 46,XY,der(21)t(21;22)(p10;q13.3). The last two patients were initially thought to have a polymorphic variant of 21p, but additional subtelomeric screening using FISH showed the extra material was derived from chromosome 22. Terminal duplications of 22qter may be more common than generally assumed, but due to its small size, especially when located on an acrocentric chromosome and/or possibly relatively mild phenotype remain undetected thus far.

CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene.

BACKGROUND: CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula. Specific behavioural problems, including autistic-like behaviour, have been described. The CHD7 gene on chromosome 8q12.1 was recently discovered as a major gene involved in the aetiology of this syndrome. METHODS: The coding regions of CHD7 were screened for mutations in 107 index patients with clinical features suggestive of CHARGE syndrome. Clinical data of the mutation positive patients were sampled to study the phenotypic spectrum of mutations in the CHD7 gene. RESULTS: Mutations were identified in 69 patients. Here we describe the clinical features of 47 of these patients, including two sib pairs. Most mutations were unique and were scattered throughout the gene. All patients but one fulfilled the current diagnostic criteria for CHARGE syndrome. No genotype-phenotype correlations were apparent in this cohort, which is best demonstrated by the differences in clinical presentation in sib pairs with identical mutations. Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism. CONCLUSIONS: CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation. In one case evidence for germline mosaicism was provided.

Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA).

BACKGROUND: Subtelomeric rearrangements contribute to idiopathic mental retardation and human malformations, sometimes as distinct mental retardation syndromes. However, for most subtelomeric defects a characteristic clinical phenotype remains to be elucidated. OBJECTIVE: To screen for submicroscopic subtelomeric aberrations using multiplex ligation dependent probe amplification (MLPA). METHODS: 210 individuals with unexplained mental retardation were studied. A new set of subtelomeric probes, the SALSA P036 human telomere test kit, was used. RESULTS: A subtelomeric aberration was identified in 14 patients (6.7%) (10 deletions and four duplications). Five deletions were de novo; four were inherited from phenotypically normal parents, suggesting that these were polymorphisms. For one deletion, DNA samples of the parents were not available. Two de novo submicroscopic duplications were detected (dup 5qter, dup 12pter), while the other duplications (dup 18qter and dup 22qter) were inherited from phenotypically similarly affected parents. All clinically relevant aberrations (de novo or inherited from similarly affected parents) occurred in patients with a clinical score of >or=3 using an established checklist for subtelomeric rearrangements. Testing of patients with a clinical score of >or=3 increased the diagnostic yield twofold to 12.4%. Abnormalities with clinical relevance occurred in 6.3%, 5.1%, and 1.7% of mildly, moderately, and severely retarded patients, respectively, indicating that testing for subtelomeric aberrations among mildly retarded individuals is necessary. CONCLUSIONS: The value of MLPA is confirmed. Subtelomeric screening can be offered to all mentally retarded patients, although clinical preselection increases the percentage of chromosomal aberrations detected. Duplications may be a more common cause of mental retardation than has been appreciated.

Chromosome 3 translocations and the risk to develop renal cell cancer: a Dutch intergroup study.

Renal cell carcinomas (RCC) occur in both sporadic and familial forms. The best known example of a familial RCC syndrome is the Von Hippel Lindau cancer syndrome. In addition, RCC families segregating constitutional chromosome 3 translocations have been reported. The list of these latter families is rapidly expanding. We have initiated a survey of all Dutch families known to segregate chromosome 3 translocations for (i) the ocurrence of RCCs and (ii) the establishment of refined risk estimates. This information will be critical for genetic counseling and clinical patient management. Within the families 'at risk' that we have identified so far, this approach has already led to early RCC detection and surgical intervention.

A new case of dup(1)(q21.2q12) in an individual with mild mental retardation.

Proximal duplications of the long arm of chromosome 1 are rare and the few patients that have been described in literature have multiple congenital abnormalities and/or mental retardation. The present paper describes the clinical and cytogenetic findings of an adult patient with only mild mental retardation and some minor malformations. The patient carries an inverted duplication of 1q12q21.2.

[Amyoplasia congenita: a serious congenital abnormality with a relatively favorable prognosis]. / Amyoplasia congenita: een ernstige congenitale afwijking met relatief gunstige prognose.

After an uneventful pregnancy a girl was born with serious joint contractures and several fractures of the long bones. The family history was negative for congenital abnormalities. Based on the distinct clinical presentation the diagnosis was 'amyoplasia', which is a partial aplasia of skeletal muscles. The cause of amyoplasia is unknown. As well as the partial muscle aplasia, which is symmetrical and mainly affects the extremities, joint contractures and deep dimples in the skin around the joints are present. Several frequently associated abnormalities have been reported, including abdominal hernias, midface capillary haemangiomas and hypoplastic external genitalia. The condition is always sporadic; there is a striking discordance within monozygotic twins and the offspring of patients is normal. In contrast with the severe neonatal presentation, the clinical prognosis is relatively good owing to intensive multidisciplinary treatment and the normal intelligence of the patients.

Interstitial 6q deletion with a Prader-Willi-like phenotype: a new case and review of the literature.

We report on an additional fourth case of Prader-Willi (PW)-like phenotype and an interstitial deletion of 6q. Despite sharing clinical characteristics, patients with a PW-like phenotype and a deletion of 6q, have features which distinguish them from Prader-Willi syndrome (PWS) patients. This case emphasizes the need to examine patients with suspected PWS, but who are negative for recognizable deletions of 15q11-q13 or uniparental maternal disomy of chromosome 15, for a deletion of 6q.

At least nine cases of trisomy 11q23-->qter in one generation as a result of familial t(11;13) translocation.

Carriers of balanced reciprocal translocations may have a (high) risk for producing liveborn children with an unbalanced karyotype. We report a large family in which a translocation between the long arm of chromosome 11 and the short arm of chromosome 13 is segregating in at least five generations. During the course of our study 15 carriers of the balanced translocation were identified and nine cases of partial trisomy of the long arm of chromosome 11 were detected during pre- and postnatal studies. Several of the patients were thoroughly clinically examined and compared with similar published cases.