WDR35 mutation in siblings with Sensenbrenner syndrome: a ciliopathy with variable phenotype.

TitleWDR35 mutation in siblings with Sensenbrenner syndrome: a ciliopathy with variable phenotype.
Publication TypeJournal Article
Year of Publication2012
AuthorsBacino, CA, Dhar, SU, Brunetti-Pierri, N, Lee, B, Bonnen, PE
JournalAm J Med Genet A
Volume158A
Issue11
Pagination2917-24
Date Published2012 Nov
ISSN1552-4833
KeywordsAmino Acid Sequence, Base Sequence, Bone and Bones, Craniosynostoses, Ectodermal Dysplasia, Exome, Female, Homozygote, Humans, Infant, Male, Mutation, Mutation, Missense, Pedigree, Phenotype, Proteins, Siblings
Abstract

Sensenbrenner syndrome and unclassified short rib-polydactyly conditions are ciliopathies with overlapping phenotypes and genetic heterogeneity. Mutations in WDR35 were identified recently in a sub-group of patients with Sensenbrenner syndrome and in a single family that presented with an unclassified form of short-rib polydactyly (SRP) syndrome. We report on siblings with an unusual combination of phenotypes: narrow thorax, short stature, minor anomalies, developmental delay, and severe hepatic fibrosis leading to liver failure and early death in two of the children. Both parents were unaffected suggesting autosomal recessive inheritance. The family and their affected children were followed over a decade. Exome sequencing was performed in one affected individual. It showed a homozygous missense mutation in a highly conserved position of the WDR35 gene. This family represents a WDR35-ciliopathy with a complex clinical presentation that includes significant overlap of the phenotypes described in Sensenbrenner syndrome and the unclassified SRPs. The accurate molecular diagnosis of this family exemplifies the power of exome sequencing in the diagnosis of Mendelian disorders and enabled us to broaden and refine our understanding of Sensenbrenner syndrome and SRP. Detailed genotype-phenotype information is provided as well as discussion of previously reported cases.

DOI10.1002/ajmg.a.35608
Alternate JournalAm. J. Med. Genet. A
PubMed ID22987818
PubMed Central IDPMC4000731
Grant ListTGM11Z04 / / Telethon / Italy
U54 HG003273 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States