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A relatively mild skeletal ciliopathy phenotype consistent with cranioectodermal dysplasia is associated with a homozygous nonsynonymous mutation in WDR35
Author(s) -
Smith Christopher,
Lamont Ryan E.,
Wade Andrew,
Bernier Francois P.,
Parboosingh Jillian S.,
Innes A. Micheil
Publication year - 2016
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.37514
Subject(s) - ciliopathy , ciliopathies , intraflagellar transport , genetics , biology , brachydactyly , cilium , exome sequencing , nonsynonymous substitution , missense mutation , disease gene identification , phenotype , joubert syndrome , ciliogenesis , mutation , consanguinity , genetic heterogeneity , short stature , gene , endocrinology , mutant , genome
Ciliopathies are a class of clinically and genetically heterogeneous disorders characterized by deficits of the primary cilium, an important organelle for cellular signaling and development. Here we report on a patient from a consanguineous family presenting with renal cysts, short stature, distinctive facial features, missing teeth, brachydactyly, narrow chest, and abnormal ribs. His phenotype resembled a skeletal ciliopathy and the initial clinical differential diagnosis included Jeune thoracic dystrophy and cranioectodermal dysplasia. Due to the presence of parental consanguinity, a homozygous recessive mutation was the suspected cause and homozygosity mapping was used to direct candidate gene sequencing. WDR35 , an intraflagellar transport protein previously associated with cranioectodermal dysplasia, the more severe short rib polydactyly syndrome type V and recently Ellis van Creveld syndrome, is present within a region of homozygosity and sequencing of all coding exons identified a novel homozygous nonsynonymous variant, p.Trp1153Cys. This variant affects a highly conserved tryptophan residue, is predicted to be deleterious, and is the most distal mutation yet reported in WDR35 . This case expands the spectrum of phenotypes caused by WDR35 mutations, which we review herein. © 2015 Wiley Periodicals, Inc.