Exome sequencing identifies pathogenic variants of VPS13B in a patient with familial 16p11.2 duplication.
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.


METHODS
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.


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.
Department of Medical Genetics, Children's and Women's Health Center of BC and Children's and Women's Health Center of BC and Univeristy of British Columbia, Vancouver, BC, V6H 3N1, Canada.|BC Children's Hospital Research Institute, Vancouver, BC, V6H 3N1, Canada.
Jila
J
Dastan
Department of Medical Genetics, Children's and Women's Health Center of BC and Children's and Women's Health Center of BC and Univeristy of British Columbia, Vancouver, BC, V6H 3N1, Canada.
Chieko
C
Chijiwa
BC Children's Hospital Research Institute, Vancouver, BC, V6H 3N1, Canada.
Flamingo
F
Tang
Department of Pathology (Cytogenetics), Children's and Women's Hopsital of BC and Children's and Women's Health Center of BC and Univeristy of British Columbia, Vancouver, BC, V5Z 4H4, Canada.|BC Children's Hospital Research Institute, Vancouver, BC, V6H 3N1, Canada.
Sally
S
Martell
Department of Medical Genetics, Children's and Women's Health Center of BC and Children's and Women's Health Center of BC and Univeristy of British Columbia, Vancouver, BC, V6H 3N1, Canada.|Department of Pathology (Cytogenetics), Children's and Women's Hopsital of BC and Children's and Women's Health Center of BC and Univeristy of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
Ying
Y
Qiao
Department of Pathology (Cytogenetics), Children's and Women's Hopsital of BC and Children's and Women's Health Center of BC and Univeristy of British Columbia, Vancouver, BC, V5Z 4H4, Canada. eseparovic@cw.bc.ca.|BC Children's Hospital Research Institute, Vancouver, BC, V6H 3N1, Canada. eseparovic@cw.bc.ca.
Evica
E
Rajcan-Separovic
Department of Medical Genetics, Children's and Women's Health Center of BC and Children's and Women's Health Center of BC and Univeristy of British Columbia, Vancouver, BC, V6H 3N1, Canada. suzanne.lewis@ubc.ca.|BC Children's Hospital Research Institute, Vancouver, BC, V6H 3N1, Canada. suzanne.lewis@ubc.ca.
M E Suzanne
MES
Lewis
D002648:Child; D002885:Chromosomes, Human, Pair 16; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics; D005385:Fingers / Q000002:abnormalities; D020440:Gene Duplication; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics; D009216:Myopia / Q000175:diagnosis / Q000235:genetics; D065886:Neurodevelopmental Disorders / Q000175:diagnosis / Q000235:genetics*; D009765:Obesity / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing; D012162:Retinal Degeneration; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics*
C475722:VPS13B protein, human; D033921:Vesicular Transport Proteins; D004247:DNA
16p11.2 duplication; Case report; Cohen syndrome; Neuro-developmental disorders; Variable expressivity; Whole exome sequencing