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

Am J Hum Genet. 2015 Apr 2;96(4):612-22. doi: 10.1016/j.ajhg.2015.02.015.

Janson White ¹, Juliana F Mazzeu ², Alexander Hoischen ³, Shalini N Jhangiani ⁴, Tomasz Gambin ⁵, Michele Calijorne Alcino ⁶, Samantha Penney ¹, Jorge M Saraiva ⁷, Hanne Hove ⁸, Flemming Skovby ⁸, Hülya Kayserili ⁹, Elicia Estrella ¹⁰, Anneke T Vulto-van Silfhout ³, Marloes Steehouwer ³, Donna M Muzny ⁴, V Reid Sutton ¹¹, Richard A Gibbs ¹², Baylor-Hopkins Center for Mendelian Genomics, James R Lupski ¹³, Han G Brunner ¹⁴, Bregje W M van Bon ³, Claudia M B Carvalho ¹⁵

Affiliations

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2 Programa de Pós-graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF 70790-160, Brazil; Robinow Syndrome Foundation, Anoka, MN 55303, USA.
3 Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
4 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Institute of Computer Science, Warsaw University of Technology, 00-661 Warsaw, Poland.
6 Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte MG 30190-002, Brazil.
7 Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075 Portugal; University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, Coimbra 3000-354, Portugal.
8 Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark.
9 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul 34093, Turkey; Medical Genetics Department, School of Medicine, Koc University, Rumelifeneri Yolu, Sariyer Istanbul 34450 Turkey.
10 Department of Genetics & Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
11 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
12 Department 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.
13 Department 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.
14 Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, 6200 AZ Maastricht, the Netherlands.
15 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte MG 30190-002, Brazil. Electronic address: [email protected].

PMID: 25817016 DOI: 10.1016/j.ajhg.2015.02.015

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.

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