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Exome sequencing identifies pathogenic variants of VPS13B in a patient with familial 16p11.2 duplication.
- Source :
-
BMC medical genetics [BMC Med Genet] 2016 Nov 10; Vol. 17 (1), pp. 78. Date of Electronic Publication: 2016 Nov 10. - Publication Year :
- 2016
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Abstract
- Background: The recurrent microduplication of 16p11.2 (dup16p11.2) is associated with a broad spectrum of neurodevelopmental disorders (NDD) confounded by incomplete penetrance and variable expressivity. This inter- and intra-familial clinical variability highlights the importance of personalized genetic counselling in individuals at-risk.<br />Case Presentation: In this study, we performed whole exome sequencing (WES) to look for other genomic alterations that could explain the clinical variability in a family with a boy presenting with NDD who inherited the dup16p11.2 from his apparently healthy mother. We identified novel splicing variants of VPS13B (8q22.2) in the proband with compound heterozygous inheritance. Two VPS13B mutations abolished the canonical splice sites resulting in low RNA expression in transformed lymphoblasts of the proband. VPS13B mutation causes Cohen syndrome (CS) consistent with the proband's phenotype (intellectual disability (ID), microcephaly, facial gestalt, retinal dystrophy, joint hypermobility and neutropenia). The new diagnosis of CS has important health implication for the proband, provides the opportunity for more meaningful and accurate genetic counselling for the family; and underscores the importance of longitudinally following patients for evolving phenotypic features.<br />Conclusions: This is the first report of a co-occurrence of pathogenic variants with familial dup16p11.2. Our finding suggests that the variable expressivity among carriers of rare putatively pathogenic CNVs such as dup16p11.2 warrants further study by WES and individualized genetic counselling of families with such CNVs.
- Subjects :
- Child
DNA chemistry
DNA isolation & purification
DNA metabolism
DNA Copy Number Variations
DNA Mutational Analysis
Developmental Disabilities diagnosis
Developmental Disabilities genetics
Fingers abnormalities
Gene Duplication
Humans
Intellectual Disability diagnosis
Intellectual Disability genetics
Male
Microcephaly diagnosis
Microcephaly genetics
Muscle Hypotonia diagnosis
Muscle Hypotonia genetics
Myopia diagnosis
Myopia genetics
Neurodevelopmental Disorders diagnosis
Obesity diagnosis
Obesity genetics
Pedigree
Phenotype
RNA Splicing
Retinal Degeneration
Retinal Dystrophies diagnosis
Retinal Dystrophies genetics
Chromosomes, Human, Pair 16
Neurodevelopmental Disorders genetics
Vesicular Transport Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2350
- Volume :
- 17
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- BMC medical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 27832746
- Full Text :
- https://doi.org/10.1186/s12881-016-0340-0