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

Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA
Universidade Catolica de Brasılia. Programa de Pos-graduaçao em Ciencias Genomicas e Biotecnologia. Brasılia, DF, Brasil/Robinow Syndrome Foundation. Anoka, MN, USA
Radboud University Medical Center. Radboud Institute for Molecular Life Sciences. Department of Human Genetics. Nijmegen, the Netherlands
Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Warsaw University of Technology. Institute of Computer Science. Warsaw, Poland
Fundaçao Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG, Brasil
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA
Centro Hospitalar e Universitario de Coimbra. Hospital Pediatrico. Medical Genetics Unit. Coimbra, Portugal/University of Coimbra. University Clinic of Pediatrics. Faculty of Medicine. Coimbra, Portugal
University of Copenhagen. Rigshospitalet. Department of Clinical Genetics. Copenhagen, Denmark
University of Copenhagen. Rigshospitalet. Department of Clinical Genetics. Copenhagen, Denmark
Istanbul University. Istanbul Medical Faculty. Medical Genetics Department. Istanbul, Turkey/Koc University, Rumelifeneri Yolu. School of Medicine. Medical Genetics Department. Sariyer Istanbul,Turkey
Boston Children’s Hospital and Harvard Medical School. Department of Genetics & Genomics. Boston, MA, USA
Radboud University Medical Center. Radboud Institute for Molecular Life Sciences. Department of Human Genetics. Nijmegen, the Netherlands
Radboud University Medical Center. Radboud Institute for Molecular Life Sciences. Department of Human Genetics. Nijmegen, the Netherlands
Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/ Texas Children’s Hospital. Houston, TX, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA/Texas Children’s Hospital. Houston, TX, USA/Baylor College of Medicine. Department of Pediatrics. Houston, TX, USA Han G. Brunner
Radboud University Medical Center. Radboud Institute for Molecular Life Sciences. Department of Human Genetics. Nijmegen, the Netherlands

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.

Keywords

Adaptor Proteins
Signal Transducing/genetics
Craniofacial Abnormalities/genetics
Frameshift Mutation/genetics
Limb Deformities, Congenital/genetics
Molecular Sequence Data
Urogenital Abnormalities/genetics

Publisher

Elsevier Inc.

Citation

WHITE, Janson et al. DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome. Am J Hum Genet., vol. 96, n. 4, p. 612-22. 2015

DOI

10.1016/j.ajhg.2015.02.015

ISSN

0002-9297

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/12561

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Open access

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