Deletions in the VPS13B (COH1) gene as a cause of Cohen syndrome.

Cohen syndrome is an autosomal recessive disorder that is characterized by mental retardation, facial dysmorphism, microcephaly, retinal dystrophy, truncal obesity, joint laxity and intermittent neutropenia. Mutations in the VPS13B (COH1) gene underlie Cohen syndrome. In approximately 70% of the patients mutations in the gene are identified on both alleles, while in about 30% only a mutation in a single allele or no mutant allele is detected. The VPS13B locus was recently added to the growing list of benign copy number variants. We hypothesized that patients with unexplained Cohen syndrome would harbour deletions affecting the VPS13B locus. We screened 35 patients from 26 families with targeted array CGH and identified 7 copy number alterations: 2 homozygous and 5 heterozygous deletions. Our results show that deletions are an important cause of Cohen syndrome and screening for copy number alterations of VPS13B should be an integral part of the diagnostic work-up of these patients. These findings have important consequences for the diagnosis of patients with genetic disorders in general since, as we highlight, rare benign copy number variants can underly autosomal recessive disorders and lead to disease in homozygous state or in compound heterozygosity with another mutation.

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.

Molecular karyotyping of patients with MCA/MR: the blurred boundary between normal and pathogenic variation.

Molecular karyotyping has revealed that microdeletions/duplications in the human genome are a major cause of multiple congenital anomalies associated with mental retardation (MCA/MR). The identification of a de novo chromosomal imbalance in a patient with MCA/MR is usually considered causal for the phenotype while a chromosomal imbalance inherited from a phenotypically normal parent is considered as a benign variation and not related to the disorder. Around 40% of imbalances in patients with MCA/MR in this series is inherited from a healthy parent and the majority of these appear to be (extremely) rare variants. As some of these contain known disease-causing genes and have also been found to be de novo in MCA/MR patients, this challenges the general view that such familial variants are innocent and of no major phenotypic consequence. Rather, we argue, that human genomes can be tolerant of genomic copy number variations depending on the genetic and environmental background and that different mechanisms play a role in determining whether these chromosomal imbalances manifest themselves.

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.

Unconventional intronic splice site mutation in SCN5A associates with cardiac sodium channelopathy.

BACKGROUND: Mutations in the cardiac sodium channel, SCN5A, have been associated with one type of long-QT syndrome, with isolated cardiac conduction defects and Brugada syndrome. The sodium channelopathies exhibit marked variation in clinical phenotypes. The mechanisms underlying the phenotypical diversity, however, remain unknown. Exonic SCN5A mutations can be detected in 20% of Brugada syndrome patients. RESULTS: An intronic mutation (c.4810+3_4810+6dupGGGT) in the SCN5A gene, located outside the consensus splice site, was detected in this study in a family with a highly variable clinical phenotype of Brugada syndrome and/or conduction disease and in a patient with Brugada syndrome. The mutation was not found in a control panel of 100 (200 alleles) ethnically matched normal control subjects. We provide in vivo and in vitro evidence that the mutation can disrupt the splice donor site, activate a cryptic splice site, and create a novel splice site. Notably, our data show that normal transcripts can be also derived from the mutant allele. CONCLUSIONS: This is the first report of an unconventional intronic splice site mutation in the SCN5A gene leading to cardiac sodium channelopathy. We speculate that its phenotypical diversity might be determined by the ratio of normal/abnormal transcripts derived from the mutant allele.

Complex chromosome re-arrangement 45,X,t(Y;9) in a girl with sex reversal and mental retardation.

A girl with mental retardation and multiple minor anomalies was found to have a complex chromosome 9p re-arrangement comprising a deleted, translocated Y chromosome, a deletion of the sex reversal gene region (DMRT1) at 9p, together with an inverted duplication of the more proximal part of 9p. The karyotype was 45,X,der(Y;9)(Ypter-->Yq12::9p21.1-->9p22.2::9p22.2-->9qter) de novo. The karyotypic male, phenotypic female had a dysgerminoma of the left dysplastic ovary. The patient had typical 'trisomy 9p' syndrome, and we propose that the critical region for this phenotype is located between 9p22.1 and 9p22.2.

De novo interstitial tandem duplication of chromosome 20p12.1p13.

We report the first case of an individual with a de novo interstitial tandem duplication of the short arm of chromosome 20p12.1p13, discuss the clinical features, and propose the possible underlying mechanism of formation.

Apparently new autosomal dominant Spondyloepimetaphyseal dysplasia: gonadal mosaicism onset.

We report a family in which an apparently previously undescribed form of Spondyloepimetaphyseal dysplasia (SEMD) presented after probable gonadal mosaicism occurred and is inherited in an autosomal dominant mode. The other autosomal dominant SEMDs are compared.

Familial adenomatous polyposis in two Black South African families.

The apparent low incidence of colon cancer in the Black population of South Africa has been ascribed to a non-Western diet. The present authors report the identification of two common 5-bp deletions at codons 1309 and 1061 of the adenomatous polyposis coli (APC) gene in a Xhosa and Zulu patient, respectively. The in vitro transcription/translation test (PTT) and a non-radioactive heteroduplex method, which facilitates resolution of enzymatically amplified DNA by agarose gel electrophoresis, were used for mutation detection. This study represents the first report of APC mutations in indigenous Black individuals clinically diagnosed with familial adenomatous polyposis coli (FAP). The two deletion mutations are responsible for FAP in 35% of affected South Africans, a frequency similar to that described in several other non-African populations. The apparently low incidence of colon cancer in the African population may be ascribed either to the rare occurrence of the 'second hit' needed for polyp formation or to a lower incidence of mutations in the APC gene.

Hemifacial microsomia in two patients further supporting chromosomal mosaicism as a causative factor.

We report two cases with hemifacial microsomia with body asymmetry associated with mosaic trisomies. The child with mosaic trisomy 9 had skin pigmentary changes. In the boy with mosaic trisomy 22, the extra chromosome 22 originated from a maternal meiosis I error.

An unbalanced translocation 46,XX,+der(18)t(18;21)(q12.2;q11.2)mat,-21 associated with maternal isodisomy 18pter-->18q12.2.

We report a patient with a 46,XX,+der(18)t(18;21)(q12.2;q11.2)mat,-21 karyotype, in whom the rarely seen adjacent-2 segregation (according to the predicted pachytene diagram model) as well as two cross-overs, resulted in maternal isodisomy 18pter-->18q12.2.

The ICF syndrome: new case and update.

The ICF syndrome: New case and update: We report the clinical progress in a 5-year-old boy with the <> (ICF) syndrome. Early diagnosis and intervention has led to a good outcome. DNMT3B mutation analysis was negative, supporting genetic heterogeneity in this condition.

The Pallister-Killian syndrome is reliably diagnosed by FISH on buccal mucosa.

The Pallister-Killian syndrome is a rare disorder, which is clinically diagnosed and usually confirmed by the detection of mosaicism for an isochromosome 12p in fibroblast cultures. To date FISH on buccal mucosa has been used in only three cases and this detected high levels of mosaicism for the isochromosome. We review one previously reported case [Woodman et al. (1995) Genet Couns 6:33-36] and report a further seven clinically suspected cases in which the diagnoses were confirmed by FISH on buccal mucosa, and recommend that this tissue be used routinely for laboratory confirmation. The presence of the isochromosome 12p at levels as low as 1% is acceptable.

Trichorhinophalangeal syndrome type II: case report.

Patients with the trichorhinophalangeal syndrome type II, also known as the Langer-Giedion syndrome, may present to the health care-givers or physicians in various specialties and need to be recognised in order that accurate diagnosis, management and counselling about prognosis and recurrence risks may be carried out. A case of young male with this condition is presented.