Title:	Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome : WNT signaling perturbation and phenotypic variability
Authors:	Chaofan Zhang Jolly, Angad Shayota, Brian J. Araújo, Juliana Forte Mazzeu de Haowei Du Dawood, Moez Soper, Patricia Celestino Lima, Ariadne Ramalho de Ferreira, Bárbara Merfort Coban-Akdemir, Zeynep White, Janson Shears, Deborah Thomson, Fraser Robert Douglas, Sarah Louise Wainwright, Andrew Bailey, Kathryn Wordsworth, Paul Oldridge, Mike Lester, Tracy Calder, Alistair D. Dumic, Katja Banka, Siddharth Donnai, Dian Jhangiani, Shalini N. Potocki, Lorraine Chung, Wendy K. Mora, Sara Northrup, Hope Ashfaq, Myla Rosenfeld, Jill A. Mason, Kati Pollack, Lynda C. McConkie-Rosell, Allyn Wei Kelly McDonald, Marie Hauser, Natalie S. Leahy, Peter Powell, Cynthia M. Boy, Raquel Honjo, Rachel Sayuri Kok, Fernando Martelli, Lucia R. Odone Filho, Vicente Genomics England Research Consortium Muzny, Donna M. Gibbs, Richard A. Posey, Jennifer E. Pengfei Liu Lupski, James R. Sutton, V. Reid Carvalho, Claudia M. B.
metadata.dc.contributor.affiliation:	BCM, Department of Molecular and Human Genetics BCM, Department of Molecular and Human Genetics BMC, Medical Scientist Training Program BCM, Department of Molecular and Human Genetics Texas Children's Hospital, Houston University of Brasilia Robinow Syndrome Foundation, Anoka BCM, Department of Molecular and Human Genetics BCM, Department of Molecular and Human Genetics BMC, Medical Scientist Training Program BCM, Human Genome Sequencing Center GeneDx Inc., Gaithersburg University of Brasilia University of Brasilia BCM, Department of Molecular and Human Genetics Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, UTHealth BCM, Department of Molecular and Human Genetics Oxford University Hospitals NHS Foundation Trust, Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Cardiothoracic Surgery NHS Lothian, Edinburgh Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust Oxford University Hospitals NHS Foundation Trust, Pediatric Rheumatology, Nuffield Orthopedic Centre Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences Oxford University Hospitals NHS Foundation Trust, Oxford Regional Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, Oxford Regional Genetics Laboratories Great Ormond Street Hospital NHS Foundation Trust, Radiology Department University Clinical Center Zagreb, Department of Pediatric Endocrinology and Diabetes The University of Manchester, School of Biological Sciences, Faculty of Biology, Medicine and Health, Division of Evolution, Infection and Genomics Manchester University NHS Foundation Trust, St Mary's Hospital, Manchester Center for Genomic Medicine, Health Innovation Manchester Manchester University NHS Foundation Trust, St Mary's Hospital, Manchester Center for Genomic Medicine, Health Innovation Manchester BCM, Human Genome Sequencing Center BCM, Department of Molecular and Human Genetics Texas Children's Hospital, Houston Columbia University, Department of Pediatrics and Medicine GeneDx Inc., Gaithersburg University of Texas Health Science Center at Houston, McGovern Medical School,Department of Pediatrics Children’s Memorial Hermann Hospital University of Texas Health Science Center at Houston, McGovern Medical School,Department of Pediatrics Children’s Memorial Hermann Hospital BCM, Department of Molecular and Human Genetics GeneDx Inc., Gaithersburg Arnold Palmer Hospital for Children, Orlando Duke University Medical Center, Division of Medical Genetics, Durham Duke University Medical Center, Division of Medical Genetics, Durham Duke University Medical Center, Division of Medical Genetics, Durham Inova Fairfax Hospital, Medical Genetics, Falls Church Cook Children's Hospital, Fort Worth University of North Carolina at Chapel Hill School of Medicine, Division of Pediatric Genetics and Metabolism State University of Rio de Janeiro University of Sao Paulo, Faculdade de Medicina, Instituto da Criança - Hospital das Clinicas HCFMUSP, Unidade de Genética Mendelics Análise Genômica, São Paulo University of Sao Paulo, Ribeirao Preto Medical School, Department of Genetics São Paulo University, Instituto de Tratamento do Câncer Infantil Hospital Israelita Albert Einstein, Medical School Queen Mary University of London, Genomics England and William Harvey Research Institute BCM, Human Genome Sequencing Center BCM, Department of Molecular and Human Genetics BCM, Human Genome Sequencing Center BCM, Department of Molecular and Human Genetics BCM, Department of Molecular and Human Genetics Baylor Genetics, Houston BCM, Department of Molecular and Human Genetics Texas Children's Hospital, Houston BCM, Human Genome Sequencing Center BCM, Department of Pediatrics BCM, Department of Molecular and Human Genetics Texas Children's Hospital, Houston BCM, Department of Molecular and Human Genetics Pacific Northwest Research Institute
Assunto::	Robinow, Síndrome de Displasia esquelética Mutação genética
Issue Date:	2022
Publisher:	Cell Press
Citation:	Human Genetics and Genomics Advances, [S. l.], n. 3, 100074, 13 jan. 2022.
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 var iants 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 pre viously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-spe cific 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 pro bands 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.
metadata.dc.description.unidade:	Faculdade de Medicina (FM)
Licença::	2021 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Appears in Collections:	Artigos publicados em periódicos e afins

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