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Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual disability and neuropathy
Author(s) -
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.
Publication year - 2017
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.38400
Subject(s) - trpv4 , compound heterozygosity , phenotype , loss function , intellectual disability , mutation , genetics , loss of heterozygosity , disease , familial hemiplegic migraine , clinical phenotype , mechanism (biology) , biology , neuroscience , medicine , transient receptor potential channel , gene , pathology , allele , receptor , philosophy , alternative medicine , epistemology , aura , migraine with aura
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.