Genomic duplication in Dyggve Melchior Clausen syndrome, a novel mutation mechanism in an autosomal recessive disorder

Kinning, Esther; Tufarelli, Cristina; Winship, W. S.; Aldred, Micheala A.; Trembath, Richard C.

doi:10.1136/jmg.2005.033829

Cited by 16 publications

(14 citation statements)

References 16 publications

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“…Nevertheless, no clear size distinction exists between benign and pathogenic CNVs. We found pathogenic CNVs as small as the 298 kb deletion of 9q34.3 in Patient 523 in this study, and others have reported even smaller pathogenic CNVs [13-15,56-58]. Expression patterns, functional annotation and animal models can provide important clues to pathogenicity in some cases, but without knowledge of the phenotypic effects of a copy number alteration in humans, one can rarely, if ever, be certain whether a novel gain or loss of a particular genomic region can produce ID or other birth defects.…”

Section: Discussionsupporting

confidence: 80%

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

et al. 2009

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BackgroundArray genomic hybridization is being used clinically to detect pathogenic copy number variants in children with intellectual disability and other birth defects. However, there is no agreement regarding the kind of array, the distribution of probes across the genome, or the resolution that is most appropriate for clinical use.ResultsWe performed 500 K Affymetrix GeneChip® array genomic hybridization in 100 idiopathic intellectual disability trios, each comprised of a child with intellectual disability of unknown cause and both unaffected parents. We found pathogenic genomic imbalance in 16 of these 100 individuals with idiopathic intellectual disability. In comparison, we had found pathogenic genomic imbalance in 11 of 100 children with idiopathic intellectual disability in a previous cohort who had been studied by 100 K GeneChip® array genomic hybridization. Among 54 intellectual disability trios selected from the previous cohort who were re-tested with 500 K GeneChip® array genomic hybridization, we identified all 10 previously-detected pathogenic genomic alterations and at least one additional pathogenic copy number variant that had not been detected with 100 K GeneChip® array genomic hybridization. Many benign copy number variants, including one that was de novo, were also detected with 500 K array genomic hybridization, but it was possible to distinguish the benign and pathogenic copy number variants with confidence in all but 3 (1.9%) of the 154 intellectual disability trios studied.ConclusionAffymetrix GeneChip® 500 K array genomic hybridization detected pathogenic genomic imbalance in 10 of 10 patients with idiopathic developmental disability in whom 100 K GeneChip® array genomic hybridization had found genomic imbalance, 1 of 44 patients in whom 100 K GeneChip® array genomic hybridization had found no abnormality, and 16 of 100 patients who had not previously been tested. Effective clinical interpretation of these studies requires considerable skill and experience.

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Section: Discussionsupporting

confidence: 80%

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

et al. 2009

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“…This observation supports the hypothesis that loss of DYM function is the likely mechanism of disease pathogenesis [13]. These mutations had been reported from unrelated DMC families from Morocco, Tunisia, Spain, Tamil, Pakistan, Portugal, Gujertia, Georgia, Chili, Argentine, Dominican Republic and Lebanon [2,5,9,11,13,14]. In the reported DYM gene mutations, more than one family from a common geographical area has been identified.…”

Section: Bpsupporting

confidence: 83%

Dyggve–Melchior–Clausen syndrome: novel splice mutation with atlanto-axial subluxation

et al. 2010

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Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive disorder characterized by the association of a progressive spondyloepimetaphyseal dysplasia and mental retardation ranging from mild to severe. The disorder results from mutations in the dymeclin (DYM) gene in the 18q12-12.1 chromosomal region. We report two siblings with classical clinical and radiological features of DMC and asymptomatic atlanto-axial dislocation. A novel homozygous splice-site mutation (IVS15+3G>T) was detected. Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed that this mutation affects normal splicing. To the best of our knowledge, this is the first report of DMC from Saudi Arabia. The splice mutation noted in our patients was compared to the previously reported cases and supports the hypothesis that loss of DYM function is the likely mechanism of disease pathogenesis. In conclusion, distinction between this type of skeletal dysplasia and Morquio disease (MPS IV) is important for paediatricians and clinical geneticist in providing standard patient care and genetic counselling.

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“…A precedent for the gain or loss of the same gene or genes giving rise to a similar phenotype is provided by deletions and duplications of the Williams-Beuren critical region, both of which result in neuronal migration defect (37). Precedents for different mutations in the same gene causing one or more conditions with different modes of inheritance are provided by the receptor tyrosine kinase-like orphan receptor 2 (ROR2 ) gene, which has been associated with both autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B (BDB1) (38), and Dymeclin (DYM), in which partial gene duplications and autosomal recessive mutations can both give rise to Dyggve-Melchior-Clausen syndrome (39).…”

Section: Discussionmentioning

confidence: 99%

Copy number changes of the microcephalin 1 gene (MCPH1) in patients with autism spectrum disorders

Özgen

Daalen²,

Bolton

et al. 2009

Clinical Genetics

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Autism spectrum disorder (ASD) represents a set of neurodevelopmental disorders with a strong genetic aetiology. Chromosomal rearrangements have been detected in 5-10% of the patients with ASD, and recent applications of array comparative genomic hybridisation (aCGH) are identifying further candidate regions and genes. In this study, we present four patients who implicate microcephalin 1 (MCPH1) in band 8p23.1 as an ASD susceptibility gene. Patient 1 was a girl with a syndromic form of autistic disorder satisfying the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS) and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Oligonucleotide aCGH (oaCGH) showed that she had a classic inv dup del(8)(qter-> p23.1::p23.1-> p21.2) containing at least three candidate genes; MCPH1 and DLGAP2 within the 6.9-Mb terminal deletion and NEF3 within the concomitant 14.1-Mb duplication. Three further patients with MCPH1 copy number changes were found using single-nucleotide polymorphism (SNP) array analysis in a cohort of 54 families with ASD patients. Our results show that ASD can be a component of the classical inv dup del(8) phenotype and identify changes in copy number of MCPH1 as a susceptibility factor for ASD in the distal short arm of chromosome 8.

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Genomic duplication in Dyggve Melchior Clausen syndrome, a novel mutation mechanism in an autosomal recessive disorder

Cited by 16 publications

References 16 publications

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

Dyggve–Melchior–Clausen syndrome: novel splice mutation with atlanto-axial subluxation

Copy number changes of the microcephalin 1 gene (MCPH1) in patients with autism spectrum disorders

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