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Contains fulltext : 292527.pdf (Publisher’s version ) (Open Access) BACKGROUND: Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. RESULTS: We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. CONCLUSION: We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques.

BackgroundHearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss.MethodsFamily and cohort studies included exome sequencing and characterisation of the hearing phenotype. Ex vivo protein expression addressed the functional effect of a DNA variant.ResultsAn in-frame deletion of 12 nucleotides in RIPOR2 was identified as a highly penetrant cause of adult-onset progressive hearing loss that segregated as an autosomal dominant trait in 12 families from the Netherlands. Hearing loss associated with the deletion in 63 subjects displayed variable audiometric characteristics and an average (SD) age of onset of 30.6 (14.9) years (range 0–70 years). A functional effect of the RIPOR2 variant was demonstrated by aberrant localisation of the mutant RIPOR2 in the stereocilia of cochlear hair cells and failure to rescue morphological defects in RIPOR2-deficient hair cells, in contrast to the wild-type protein. Strikingly, the RIPOR2 variant is present in 18 of 22 952 individuals not selected for hearing loss in the Southeast Netherlands.ConclusionCollectively, the presented data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy.

De novo mutations in protein-coding genes are a well-established cause of developmental disorders. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.

ATP2B2 encodes the PMCA2 Ca2+ pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca2+ from the stereocilia to the endolymph. Several mouse models have been described for this gene; mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment. Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2. Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo. Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment. After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3–6 years. Subjects had no balance complaints and vestibular testing did not yield abnormalities. There was no evidence for retrocochlear pathology or structural inner ear abnormalities. Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2. Electronic supplementary material The online version of this article (10.1007/s00439-018-1965-1) contains supplementary material, which is available to authorized users.

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Contains fulltext : 182761.pdf (Publisher’s version ) (Open Access) Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip. Recently, causative compound heterozygous variants were identified in TXNL4A. We analyzed an individual with clinical features of BMKS and her parents by whole-genome sequencing and identified compound heterozygous variants in TXNL4A (a novel splice site variant (c.258-2A>G, (p.?)) and a 34 bp promoter deletion (hg19 chr18:g.77748581_77748614del (type 1Delta) in the proband). Subsequently, we tested a cohort of 19 individuals with (mild) features of BMKS and 17 individuals with isolated choanal atresia for causative variants in TXNL4A by dideoxy-sequence analysis. In one individual with BMKS unrelated to the first family, we identified the identical compound heterozygous variants. In an individual with isolated choanal atresia, we found homozygosity for the same type 1Delta promoter deletion, whilst in two cousins from a family with choanal atresia and other minor anomalies we found homozygosity for a different deletion within the promoter (hg19 chr18: g.77748604_77748637del (type 2Delta)). Hence, we identified causative recessive variants in TXNL4A in two individuals with BMKS as well as in three individuals (from two families) with isolated choanal atresia.

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Contains fulltext : 137231.pdf (Publisher’s version ) (Open Access) X-linked sideroblastic anemia (XLSA) is the most common form of congenital sideroblastic anemia. In affected males, it is uniformly associated with partial loss-of-function missense mutations in the erythroid-specific heme biosynthesis protein 5-aminolevulinate synthase 2 (ALAS2). Here, we report five families with XLSA owing to mutations in a GATA transcription factor binding site located in a transcriptional enhancer element in intron 1 of the ALAS2 gene. As such, this study defines a new class of mutations that should be evaluated in patients undergoing genetic testing for a suspected diagnosis of XLSA. Am. J. Hematol. 89:315-319, 2014. (c) 2013 Wiley Periodicals, Inc.

Contains fulltext : 124659.pdf (Publisher’s version ) (Open Access) CONTEXT: Unbalanced subtelomeric chromosomal rearrangements are often associated with intellectual disability (ID) and malformation syndromes. The prevalence of such rearrangements has been reported to be 5-9% in ID populations. AIMS: To study the prevalence of subtelomeric rearrangements in the Indonesian ID population. MATERIALS AND METHODS: We tested 436 subjects with unexplained ID using multiplex ligation dependent probe amplification (MLPA) using the specific designed sets of probes to detect human subtelomeric chromosomal imbalances (SALSA P070 and P036D). If necessary, abnormal findings were confirmed by other MLPA probe kits, fluorescent in situ hybridization or Single Nucleotide Polymorphism array. RESULTS: A subtelomeric aberration was identified in 3.7% of patients (16/436). Details on subtelomeric aberrations and confirmation analyses are discussed. CONCLUSION: This is the first study describing the presence of subtelomeric rearrangements in individuals with ID in Indonesia. Furthermore, it shows that also in Indonesia such abnormalities are a prime cause of ID and that in developing countries with limited diagnostic services such as Indonesia, it is important and feasible to uncover the genetic etiology in a significant number of cases with ID.

Item does not contain fulltext Fragile X-associated disorders caused by the premutation of the FMR1 gene, includes the fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS affects more than 40% of premutation males over the age of 50 and 75% over the age of 80. FMR1 molecular analysis was done using PCR and confirmed by Southern Blot. Three premutation males were diagnosed FXTAS using quantification based on the standard neurological examination. Cognitive impairment was assessed using Raven and WAIS-R test. MRI was done to identify the middle cerebellar peduncle (MCP) sign, white matter disease and/or cerebral atrophy. Three cases of FXTAS are identified, of five individuals older than 50 years in one family tree two met criteria for definite FXTAS and the third with sub-clinical symptoms, although cognitive and radiological criteria are met. These cases are the first identified FXTAS cases in rural Indonesia. In addition with lack of routine medical follow-up, complications of FXTAS, such as hypertension may go unrecognized and untreated, which may further exacerbate the central nervous system (CNS) findings of FXTAS.

Contains fulltext : 108738.pdf (Publisher’s version ) (Open Access) Mowat-Wilson syndrome (OMIM 235730) is a genetic condition characterized by moderate-to-severe intellectual disability, a recognizable facial phenotype, and multiple congenital anomalies. The striking facial phenotype in addition to other features such as severely impaired speech, hypotonia, microcephaly, short stature, seizures, corpus callosum agenesis, congenital heart defects, hypospadias, and Hirschsprung disease are particularly important clues for the initial clinical diagnosis. All molecularly confirmed cases with typical MWS have a heterozygous loss-of-function mutation in the zinc finger E-box protein 2 (ZEB2) gene, also called SIP1 (Smad-interacting protein 1) and ZFHX1B, suggesting that haploinsufficiency is the main pathological mechanism. Approximately 80% of mutations are nonsense and frameshift mutations (small insertions or deletions). About half of these mutations are located in exon eight. Here, we report the first Indonesian patient with Mowat-Wilson syndrome confirmed by molecular analysis.

Item does not contain fulltext AIM: To assess cardiac anatomy and myocardial systolic function in children with Prader-Willi syndrome (PWS). METHODS: Physical examination, electrocardiographic (ECG) recordings and transthoracic echocardiograms including two-dimensional speckle tracking echocardiography (2DSTE) were performed and evaluated in the Radboud University Hospital Nijmegen, the Netherlands. In total, 19 children diagnosed with PWS and 38 age-matched control subjects underwent cardiac evaluation. RESULTS: Abnormal ECG findings were detected in nine PWS patients. Echocardiography revealed mild structural cardiac abnormalities in two patients. Conventional echocardiographic findings did not indicate systolic left ventricular dysfunction, in contrast to 2DSTE examination. Global peak systolic strain (rate) measurements, in all three directions of contraction, were significantly lower in children with PWS (p < 0.001) compared with healthy age-matched children. In two-thirds of the patients, 2DSTE revealed abnormal systolic deformation (peak systolic strain as well as strain rate). T2P values in PWS patients were similar to control subject. Systolic myocardial function appears more affected in case of maternal uniparental disomy. CONCLUSION: Cardiac evaluation, including 2DSTE, detects frequent alterations in myocardial systolic function in children diagnosed with PWS, whose conventional echocardiographic findings did not indicate ventricular systolic dysfunction. Because cardiovascular morbidity and mortality is substantial in PWS, especially adults, we emphasize the need for cardiac assessment in PWS. 01 mei 2012

Item does not contain fulltext Ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome is the prototype of several p63 conditions, which include ankyloblepharon, ectodermal dysplasia, clefting (AEC) syndrome, limb-mammary syndrome (LMS), Rapp-Hodgkin syndrome (RHS), ADULT syndrome, and others. All these disorders include combinations of ectodermal dysplasia, orofacial clefting and limb malformations in variable severity. A newborn patient is presented with diffuse erythematous and desquamating skin lesions and anal atresia. She also had sparse and lightly colored thin hair, deeply set eyes, hypoplastic alae nasi, and a short philtrum. Cleft lip/palate and ankyloblepharon were not present. Complete cutaneous syndactyly was present on both hands in between the third and fourth fingers. Mild ectrodactyly was evident on all four extremities in between first and second digits. There was post-axial polydactyly on both feet. Anal atresia was present and defecation occurred through a rectovaginal fistula. The patient represented an interesting overlapping clinical condition between AEC and EEC syndromes. Diffuse skin lesions with excoriation and desquamation suggest AEC syndrome, despite the absence of ankyloblepharon, however; ectrodactyly and polydactyly strongly suggest the EEC syndrome. C308Y mutation in exon 8 of TP63 gene was detected, which was previously described to lead only to EEC syndrome and not to any of the other allelic conditions. These data emphasize the large degree of clinical variability that may be seen for specific TP63 mutations. (c) 2011 Wiley Periodicals, Inc.

Contains fulltext : 58370.pdf (Publisher’s version ) (Closed access) Recently, the polyglutamine-binding protein 1 (PQBP1) gene was found to be mutated in five of 29 families studied with X-linked mental retardation (XLMR) linked to Xp. The reported mutations include duplications or deletions of AG dinucleotides in the fourth coding exon that resulted in shifts of the open reading frame. Three of the five families with mutations in this newly identified XLMR gene have been reported previously. We characterized the phenotypic and neuropsychological features in the two unpublished families with aberrations in PQBP1 and in a family reported 10 years ago. In total, seven patients diagnosed with aberrations in this gene were examined, including a newly identified patient at 18 months of age. Additionally, the features were compared to those reported in the literature of three other families, comprising MRXS3 (Sutherland-Haan syndrome) MRX55 and MRXS8 (Renpenning syndrome). Characteristics seen in these patients are microcephaly, lean body habitus, short stature, striking facial appearance with long narrow faces, upward slant of the eyes, malar hypoplasia, prognathism, high-arched palate and nasal speech. In addition, small testes and midline defects as anal atresia or imperforate anus, clefting of palate and/or uvula, iris coloboma and Tetralogy of Fallot are seen in several patients. These observations contribute to the phenotypic knowledge of patients with PQBP1 mutations and make this XLMR syndrome well recognizable to clinicians.

Item does not contain fulltext KUN, 07 november 2001 Promotor : Brunner, H.G.

Contains fulltext : 28120.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 105789.pdf (Publisher’s version ) (Open Access) Intellectual disability (ID) has been defined as a significant limitation in both intellectual functioning (IQ