Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability
Year: 2021
Type: article
Study design: Observational Study
Abstract: Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.
Authors: Chaofan Zhang, Angad Jolly, Brian J. Shayota, Juliana F. Mazzeu, Haowei Du, Moez Dawood, Patricia Celestino Soper, Ariadne Ramalho de Lima, Bárbara Merfort Ferreira, Zeynep Coban-Akdemir, Janson White, Deborah Shears, Fraser Robert Thomson, Sarah Louise Douglas, Andrew Wainwright, Kathryn Bailey, Paul Wordsworth, Mike Oldridge, Tracy Lester, Alistair D. Calder, Katja Dumic, Siddharth Banka, Dian Donnai, Shalini N. Jhangiani, Lorraine Potocki, Wendy K. Chung, Sara Mora, Hope Northrup, Myla Ashfaq, Jill A. Rosenfeld, Kati Mason, Lynda C. Pollack, Allyn McConkie-Rosell, Wei Kelly, Marie McDonald, Natalie S. Hauser, Peter Leahy, Cynthia M. Powell, Raquel Boy, Rachel Sayuri Honjo, Fernando Kok, Lucia R. Martelli, Vicente Odone Filho, Donna M. Muzny, Richard A. Gibbs, Jennifer E. Posey, Pengfei Liu, James R. Lupski, V. Reid Sutton, Claudia M.B. Carvalho
Institutions: Baylor College of Medicine, Texas Children's Hospital, Universidade de Brasília, The University of Texas Health Science Center at Houston, Oxford University Hospitals NHS Trust, NHS Lothian, Nuffield Orthopaedic Centre, Great Ormond Street Hospital, University Hospital Centre Zagreb, University of Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Columbia University, Memorial Hermann, Arnold Palmer Hospital for Children, Duke Medical Center, Inova Fairfax Hospital, Cook Children's Medical Center, University of North Carolina at Chapel Hill, Universidade do Estado do Rio de Janeiro, Universidade de São Paulo, Mendelics, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Hospital Israelita Albert Einstein, Baylor Genetics
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,000
Funders: ACMG Foundation for Genetic and Genomic Medicine, JPB Foundation, Johns Hopkins University, Wellcome Trust, Heart of England NHS Foundation Trust, Baylor-Hopkins Center for Mendelian Genomics, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, National Institutes of Health, Medical Research Council, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1114968445, Discovery and functional characterization of genic variants leading to Robinow syndrome and related skeletal dysplasias., G1169169634, G1214820642, G1403729228, G1462636319, G1920747571, G2127337682, G2274169641, Individual genomic analyses to discover the molecular basis and mechanisms contributing to adult-onset disease, G2780988280, G3153718366, G3564106781, G368261771, G4063265, G9000032418, G9000049010, G9000060819, G9000100747, Medical Genetics Research Fellowship Program
OpenAlex ID: W4200537979