Fryns Jp

Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports

Background: Chromosomal abnormalities are a major cause of mental retardation and multiple congenital anomalies (MCA/MR). Screening for these chromosomal imbalances has mainly been done by standard karyotyping. Previous array CGH studies on selected patients with chromosomal phenotypes and normal karyotypes suggested an incidence of 10–15% of previously unnoticed de novo chromosomal imbalances. Objective: To report array CGH screening of a series of 140 patients (the largest published so far) with idiopathic MCA/MR but normal karyotype. Results: Submicroscopic chromosomal imbalances were detected in 28 of the 140 patients (20%) and included 18 deletions, seven duplications, and three unbalanced translocations. Seventeen of 24 imbalances were confirmed de novo and 19 were assumed to be causal. Excluding subtelomeric imbalances, our study identified 11 clinically relevant interstitial submicroscopic imbalances (8%). Taking this and previously reported studies into consideration, array CGH screening with a resolution of at least 1 Mb has been undertaken on 432 patients with MCA/MR. Most imbalances are non-recurrent and spread across the genome. In at least 8.8% of these patients (38 of 432) de novo intrachromosomal alterations have been identified. Conclusions: Array CGH should be considered an essential aspect of the genetic analysis of patients with MCA/MR. In addition, in the present study three patients were mosaic for a structural chromosome rearrangement. One of these patients had monosomy 7 in as few as 8% of the cells, showing that array CGH allows detection of low grade mosaicisims.

Recurrent reciprocal deletions and duplications of 16p13.11: The deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant

Background: Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16. Methods and Results: A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. Fine mapping by high-resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population showed that 16p13.11 deletions are significantly associated with MR/MCA (pu200a=u200a0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%). Conclusion: These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients’ phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling.

Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome.

The expression of a gene requires not only a normal coding sequence but also intact regulatory regions, which can be located at large distances from the target genes, as demonstrated for an increasing number of developmental genes. In previous mutation studies of the role of FOXL2 in blepharophimosis syndrome (BPES), we identified intragenic mutations in 70% of our patients. Three translocation breakpoints upstream of FOXL2 in patients with BPES suggested a position effect. Here, we identified novel microdeletions outside of FOXL2 in cases of sporadic and familial BPES. Specifically, four rearrangements, with an overlap of 126 kb, are located 230 kb upstream of FOXL2, telomeric to the reported translocation breakpoints. Moreover, the shortest region of deletion overlap (SRO) contains several conserved nongenic sequences (CNGs) harboring putative transcription-factor binding sites and representing potential long-range cis-regulatory elements. Interestingly, the human region orthologous to the 12-kb sequence deleted in the polled intersex syndrome in goat, which is an animal model for BPES, is contained in this SRO, providing evidence of human-goat conservation of FOXL2 expression and of the mutational mechanism. Surprisingly, in a fifth family with BPES, one rearrangement was found downstream of FOXL2. In addition, we report nine novel rearrangements encompassing FOXL2 that range from partial gene deletions to submicroscopic deletions. Overall, genomic rearrangements encompassing or outside of FOXL2 account for 16% of all molecular defects found in our families with BPES. In summary, this is the first report of extragenic deletions in BPES, providing further evidence of potential long-range cis-regulatory elements regulating FOXL2 expression. It contributes to the enlarging group of developmental diseases caused by defective distant regulation of gene expression. Finally, we demonstrate that CNGs are candidate regions for genomic rearrangements in developmental genes.

THE KABUKI (NIIKAWA-KUROKI) SYNDROME - FURTHER DELINEATION OF THE PHENOTYPE IN 29 NON-JAPANESE PATIENTS

The Kabuki (Niikawa-Kuroki) syndrome was reported in 1981 by Niikawa et al. [19] and Kuroki et al. [15] in a total of ten unrelated Japanese children with a characteristic array of multiple congenital anomalies and mental retardation. The syndrome is characterized by a distinct face, mild to moderate mental retardation, postnatal growth retardation, dermatoglyphic and skeletal abnormalities. In Japan, the syndrome appears to have an incidence of about 1∶32 000 newborns. Outside of Japan, a growing number of patients have been recognized. Clinical data are presented on 29 Caucasian patients; the patients were diagnosed over a relatively short period of time, indicating that the incidence outside of Japan is probably not lower than in Japan. A literature review of 89 patients (60 Japanese and 29 non-Japanese) is given. In 66% of the non-Japanese patients serious neurological problems were present, most notably hypotonia and feeding problems (which were not only related to the cleft palate); this was not reported in the Japanese patients. Inheritance is not clear. Most patients are isolated, sex-ratio is equal. The syndrome can be recognized in patients with cleft (lip/)palate, with mild to moderate developmental delay and in young children with hypotonia and/or feeding problems. In counselling parents, the designation “Kabuki” syndrome seems to be more appropriate than “Kabuki make-up” syndrome.

The neurobeachin gene is disrupted by a translocation in a patient with idiopathic autism

Autism is a developmental disorder characterised by a triad of clearly abnormal or impaired development in social interaction and communication, and a markedly restricted repertoire of activity and interests.1 Its incidence is estimated at about 1/1000 to 1/2000.2 Different metabolic and structural brain anomalies have been observed in subjects with autism but these data have not yet led to a single unifying theory on its pathogenesis. In a minority (5–10%) of cases, autism is a symptom of a recognisable disorder such as fragile X syndrome, tuberous sclerosis, or untreated phenylketonuria.3 However, the molecular pathways involved in these disorders have also not contributed to an increased understanding of the pathogenesis of autism. In the majority of cases, the cause of autism is not known but there is strong evidence for a genetic cause. A polygenic inheritance is likely but estimates on the number of interacting genes vary from two to 10.4,5 Moreover, it is likely that different combinations of genes are implicated in unrelated subjects.6 The identification of genes involved in autism is expected to increase our understanding of the pathogenesis of this disorder. Several large scale linkage studies and follow up analyses have yielded suggestive linkage to several different chromosomal regions. However, neither this approach nor the large number of association studies using candidate genes has resulted in the identification of autism susceptibility genes.5 As an alternative approach to identifying candidate genes for autism, we initiated a positional cloning strategy starting with subjects with autism carrying a de novo chromosomal anomaly. In a group of 525 subjects with autism who were karyotyped and had no recognised underlying medical condition, four were found to carry such a de novo chromosomal aberration. In none of them was there a family history of autism. Three had …

Zinc finger 81 (ZNF81) mutations associated with X-linked mental retardation

X-linked mental retardation (XLMR) has a prevalence of 2.6 cases per 1000 population, accounting for over 10% of all cases of mental retardation. Clinically, XLMR exists in syndromic (MRXS) and non-syndromic (MRX) forms, that is without other distinguishing features.nnNon-syndromic X-linked mental retardation (MRX) is a highly heterogeneous group of conditions in which mental retardation (MR) is the only consistent clinical feature in patients. This in contrast to syndromic forms of X-linked mental retardation (MRXS), where MR is associated with recognisable clinical signs such as congenital malformations, neurological features, or metabolic disturbances. Identifying novel genes that are responsible for MRX is difficult due to the heterogeneity of this disorder. At present 30 genes have been identified as playing a role in MRXS. However in MRX, only 15 genes are known to be involved accounting for less than one-fifth of all MRX.1–6 The recent observations that RSK2, MECP2 , and ARX play a role in both syndromic and non-syndromic forms of XLMR,7–10 suggest that a molecular basis to strictly separate these two forms is not always present. In addition, careful clinical re-examination of patients with an OPHN1 gene mutation has revealed distinctive phenotypic hallmarks, such as cerebellar hypoplasia, in patients who were previously classified as non-syndromic.11,12nnThe frequency of causative mutations in any of the 15 MRX genes known today appears to be very low, so in the majority of patients with MRX the genetic cause is still not known. It has been suggested that up to 100 different genes might be involved in MRX.1–4 Seven of the 15 genes have been cloned on the basis of their disruption by chromosomal rearrangements in mentally retarded patients. Recently, it has been predicted that approximately 30% of all mutations underlying MRX are located in the …

Origins of the fragile X syndrome mutation.

The fragile X syndrome is a common cause of mental impairment. In view of the low reproductive fitness of affected males, the high incidence of the syndrome has been suggested to be the result of a high rate of new mutations occurring exclusively in the male germline. Extensive family studies, however, have failed to identify any cases of a new mutation. Alternatively, it has been suggested that a selective advantage of unaffected heterozygotes may, in part, explain the high incidence of the syndrome. Molecular investigations have shown that the syndrome is caused by the amplification of a CGG trinucleotide repeat in the FMR-1 gene which leads to the loss of gene expression. Further to this, genetic studies have suggested that there is evidence of linkage disequilibrium between the fragile X disease locus and flanking polymorphic markers. More recently, this analysis has been extended and has led to the observation that a large number of fragile X chromosomes appear to be lineage descendants of founder mutation events. Here, we present a study of the FRAXAC1 polymorphic marker in our patient cohort. We find that its allele distribution is strikingly different on fragile X chromosomes, confirming the earlier observations and giving further support to the suggestions of a fragile X founder effect.

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.

Congenital scalp defects with distal limb reduction anomalies.

Congenital scalp defects and distal limb reduction anomalies can occur as separate entities or in combination with other anomalies. They also occur together in an apparently autosomal dominant syndrome, an example of which is described in the present paper. The literature on the subject is reviewed.

The facial dysmorphy in the newly recognised microdeletion 2p15–p16.1 refined to a 570 kb region in 2p15

In this journal, Rajcan-Separovic et al 1 characterised a new microdeletion syndrome involving chromosome 2p15–16.1 in two patients with an autistic disorder (AD) and multiple congenital anomalies (MCA) with recognisable dysmorphic features. While screening for genomic copy number variations with a 1 Mb resolution bacterial artificial chromosome (BAC) array-based comparative genomic hybridisation (aCGH) in patients referred for the aetiological diagnosis of mental retardation and MCA (MR/MCA), a 570 kb de novo microdeletion at 2p15 was detected. We compare our findings with those of Rajcan-Separovic et al 1 and we discuss the phenotype–genotype correlations.nnThe patient is a 16-year-old boy born to healthy and non-consanguineous Belgian parents. nnHe was first referred at the age of 9½ years (fig 1A) for school difficulties secondary to mild mental retardation (IQ of 50), MCA with ectomorphic habitus (height 147 cm (>P97), weight 25.7 kg (P3) and a normal occipito-frontal circumference of 54.2 cm). He has characteristic dysmorphic features including high forehead, fine hair, telecanthus, antimongoloid palpebral fissures, large ears, broad and high nasal root with prominent tip, high palate with nasal speech, everted lower lip, long fingers, pectus excavatum, kyphoscoliosis (>20°), congenital heart defect consisting of a bicuspid aortic valve with mild aortic valve insufficiency without stenosis and a prolapsed mitral valve with a first grade mitral …