DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.

TitleDVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.
Publication TypeJournal Article
Year of Publication2016
AuthorsWhite, JJ, Mazzeu, JF, Hoischen, A, Bayram, Y, Withers, M, Gezdirici, A, Kimonis, V, Steehouwer, M, Jhangiani, SN, Muzny, DM, Gibbs, RA, van Bon, BWM, V Sutton, R, Lupski, JR, Brunner, HG, Carvalho, CMB
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2016 Mar 03
KeywordsAdaptor Proteins, Signal Transducing, Alleles, Base Sequence, Codon, Nonsense, Craniofacial Abnormalities, Dishevelled Proteins, Dwarfism, Exons, Female, Frameshift Mutation, Genetic Variation, Humans, Limb Deformities, Congenital, Male, Molecular Sequence Data, Phosphoproteins, Proto-Oncogene Proteins, Receptor Tyrosine Kinase-like Orphan Receptors, Sequence Analysis, DNA, Sequence Deletion, Urogenital Abnormalities, Wnt Proteins, Wnt-5a Protein

Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a -1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow syndrome, all variants in DVL3 result in a -1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations.

Alternate JournalAm J Hum Genet
PubMed ID26924530
PubMed Central IDPMC4800044
Grant ListT32 GM008307 / GM / NIGMS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States

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