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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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