DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal-Dominant Robinow Syndrome

Janson White, Juliana F. Mazzeu, Alexander Hoischen, Shalini N. Jhangiani, Tomasz Gambin, Michele Calijorne Alcino, Samantha Penney, Jorge M. Saraiva, Hanne Hove, Flemming Skovby, Hulya Kayserili, Elicia Estrella, Anneke T. Vulto-van Silfhout, Marloes Steehouwer, Donna M. Muzny, V. Reid Sutton, Richard A. Gibbs, James R. Lupski, Han G. Brunner, Bregje W. M. van BonClaudia M. B. Carvalho*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

80 Citations (Web of Science)

Abstract

Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.
Original languageEnglish
Pages (from-to)612-622
JournalAmerican Journal of Human Genetics
Volume96
Issue number4
DOIs
Publication statusPublished - 2 Apr 2015

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