Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual disability and neuropathy

TRPV4 encodes a polymodal calcium‐permeable plasma membrane channel. Dominant pathogenic mutations in TRPV4 lead to a wide spectrum of abnormal phenotypes. This is the first report of biallelic TRPV4 mutations and we describe two compound heterozygous siblings presenting with a complex phenotype inc...

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Bibliographic Details
Published in:American journal of medical genetics. Part A 2017-11, Vol.173 (11), p.3087-3092
Main Authors: Thibodeau, My Linh, Peters, Colin H., Townsend, Katelin N., Shen, Yaoqing, Hendson, Glenda, Adam, Shelin, Selby, Kathryn, Macleod, Patrick M., Gershome, Cynthia, Ruben, Peter, Jones, Steven J. M., Friedman, Jan M., Gibson, William T., Horvath, Gabriella A.
Format: Article
Language:English
Subjects:
brachydactyly
Brain - growth & development
Brain - pathology
Calcium
Calcium permeability
channelopathy
Children
Female
Genetic Predisposition to Disease
hearing loss
Heredity
Heterozygosity
Humans
Infant
Intellectual disabilities
intellectual disability
Intellectual Disability - genetics
Intellectual Disability - physiopathology
Male
Mutation
Mutation, Missense
neuromuscular diseases
Neuromuscular Diseases - genetics
Neuromuscular Diseases - physiopathology
Neuropathy
Peripheral Nervous System Diseases - genetics
Peripheral Nervous System Diseases - physiopathology
peripheral neuropathy
Phenotype
retinopathy
scoliosis
Siblings
skeletal
TRPV Cation Channels - genetics
TRPV4
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Summary:TRPV4 encodes a polymodal calcium‐permeable plasma membrane channel. Dominant pathogenic mutations in TRPV4 lead to a wide spectrum of abnormal phenotypes. This is the first report of biallelic TRPV4 mutations and we describe two compound heterozygous siblings presenting with a complex phenotype including severe neuromuscular involvement. In light of previously well described dominant inheritance for TRPV4‐related neuromuscular disease, our study suggests a role for compound heterozygosity and loss‐of‐function as a potential novel disease mechanism for this group of disorders. Profound intellectual disability was also noted in both affected children, suggesting that TRPV4 may be necessary for normal brain development.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.38400