DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.

TitleDVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.
Publication TypeJournal Article
Year of Publication2015
AuthorsWhite, J, Mazzeu, JF, Hoischen, A, Jhangiani, SN, Gambin, T, Alcino, MCalijorne, Penney, S, Saraiva, JM, Hove, H, Skovby, F, Kayserili, H, Estrella, E, van Silfhout, ATVulto-, Steehouwer, M, Muzny, DM, V Sutton, R, Gibbs, RA, Lupski, JR, Brunner, HG, van Bon, BWM, Carvalho, CMB
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2015 Apr 02
KeywordsAdaptor Proteins, Signal Transducing, Amino Acid Sequence, Base Sequence, Craniofacial Abnormalities, Dishevelled Proteins, DNA Primers, Dwarfism, Exome, Exons, Frameshift Mutation, Gene Components, Humans, Limb Deformities, Congenital, Molecular Sequence Data, Phosphoproteins, Sequence Analysis, DNA, Urogenital Abnormalities

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.

Alternate JournalAm J Hum Genet
PubMed ID25817016
PubMed Central IDPMC4385180
Grant ListU54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG003273 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States

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