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

Janson J. White, Juliana E. Mazzeu, Alexander Hoischen, Yavuz Bayram, Marjorie Withers, Alper Gezdirici, Virginia Kimonis, Marloes Steehouwer, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, Bregje W. M. van Bon, V. Reid Sutton, James R. Lupski, Han G. Brunner*, Claudia M. B. Carvalho*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 DVLI-mediated Robinow syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVLI 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 DVLI-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 DVLI- and DVL3-mediated Robinow syndrome and further elucidate the phenotypic features present in subjects with DVLI and DVL3 frameshift mutations.
Original languageEnglish
Pages (from-to)553-561
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - 3 Mar 2016

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