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Am J Hum Genet. 2016 Mar 3;98(3):553-61. doi: 10.1016/j.ajhg.2016.01.005. Epub 2016 Feb 25.

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

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  • 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2Faculdade de Medicina, Universidade de Brasília, Brasília DF 70910900, Brazil; Robinow Syndrome Foundation, Anoka, MN 55303, USA.
  • 3Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 4Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey.
  • 5Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Orange, CA 92868, USA.
  • 6Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 7Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 8Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 9Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 10Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands. Electronic address: han.brunner@radboudumc.nl.
  • 11Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: cfonseca@bcm.edu.

Abstract

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.

PMID:
26924530
PMCID:
PMC4800044
DOI:
10.1016/j.ajhg.2016.01.005
[PubMed - indexed for MEDLINE]
Free PMC Article
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