HGG Advances (Jan 2022)
Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability
- 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,
- Genomics England Research Consortium,
- Donna M. Muzny,
- Richard A. Gibbs,
- Jennifer E. Posey,
- Pengfei Liu,
- James R. Lupski,
- V. Reid Sutton,
- Claudia M.B. Carvalho
Affiliations
- Chaofan Zhang
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA
- Angad Jolly
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Medical Scientist Training Program, BCM, Houston, TX 77030, USA
- Brian J. Shayota
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA
- Juliana F. Mazzeu
- University of Brasilia, Brasilia 70050, Brazil; Robinow Syndrome Foundation, Anoka, MN 55303, USA
- Haowei Du
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA
- Moez Dawood
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Medical Scientist Training Program, BCM, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA
- Patricia Celestino Soper
- GeneDx Inc., Gaithersburg, MD 20878, USA
- Ariadne Ramalho de Lima
- University of Brasilia, Brasilia 70050, Brazil
- Bárbara Merfort Ferreira
- University of Brasilia, Brasilia 70050, Brazil
- Zeynep Coban-Akdemir
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, UTHealth, Houston, TX 77030, USA
- Janson White
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA
- Deborah Shears
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK
- Fraser Robert Thomson
- Cardiothoracic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK
- Sarah Louise Douglas
- NHS Lothian, Edinburgh EH1 3EG, UK
- Andrew Wainwright
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK
- Kathryn Bailey
- Pediatric Rheumatology, Nuffield Orthopedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK
- Paul Wordsworth
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Oxford OX3 7LD, UK
- Mike Oldridge
- Oxford Regional Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
- Tracy Lester
- Oxford Regional Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
- Alistair D. Calder
- Radiology Department, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK
- Katja Dumic
- Department of Pediatric Endocrinology and Diabetes, University Clinical Center Zagreb, Zagreb 10000, Croatia
- Siddharth Banka
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK; Manchester Center for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK
- Dian Donnai
- Manchester Center for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK
- Shalini N. Jhangiani
- Human Genome Sequencing Center, BCM, Houston, TX 77030, USA
- Lorraine Potocki
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA
- Wendy K. Chung
- Department of Pediatrics and Medicine, Columbia University, NY 10032, USA
- Sara Mora
- GeneDx Inc., Gaithersburg, MD 20878, USA
- Hope Northrup
- Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children’s Memorial Hermann Hospital, Houston, TX 77030, USA
- Myla Ashfaq
- Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children’s Memorial Hermann Hospital, Houston, TX 77030, USA
- Jill A. Rosenfeld
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA
- Kati Mason
- GeneDx Inc., Gaithersburg, MD 20878, USA; Arnold Palmer Hospital for Children, Orlando, FL 32806, USA
- Lynda C. Pollack
- Arnold Palmer Hospital for Children, Orlando, FL 32806, USA
- Allyn McConkie-Rosell
- Division of Medical Genetics, Duke University Medical Center, Durham, NC 27708, USA
- Wei Kelly
- Division of Medical Genetics, Duke University Medical Center, Durham, NC 27708, USA
- Marie McDonald
- Division of Medical Genetics, Duke University Medical Center, Durham, NC 27708, USA
- Natalie S. Hauser
- Medical Genetics, Inova Fairfax Hospital, Falls Church, VA 22042, USA
- Peter Leahy
- Cook Children's Hospital, Fort Worth, TX 76104, USA
- Cynthia M. Powell
- Division of Pediatric Genetics and Metabolism, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
- Raquel Boy
- State University of Rio de Janeiro, Rio de Janeiro 21941, Brazil
- Rachel Sayuri Honjo
- Unidade de Genética, Instituto da Criança - Hospital das Clinicas HCFMUSP, Faculdade de Medicina, University of Sao Paulo, São Paulo 05508, Brasil
- Fernando Kok
- Mendelics Análise Genômica, São Paulo 04013, Brasil
- Lucia R. Martelli
- Department of Genetics, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo 05508, Brazil
- Vicente Odone Filho
- Instituto de Tratamento do Câncer Infantil, São Paulo University Medical School, Hospital Israelita Albert Einstein, São Paulo 05508, Brasil
- Genomics England Research Consortium
- Genomics England and William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK
- Donna M. Muzny
- Human Genome Sequencing Center, BCM, Houston, TX 77030, USA
- Richard A. Gibbs
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA
- Jennifer E. Posey
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA
- Pengfei Liu
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA
- James R. Lupski
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA; Department of Pediatrics, BCM, Houston, TX 77030, USA
- V. Reid Sutton
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA
- Claudia M.B. Carvalho
- Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Pacific Northwest Research Institute (PNRI), Seattle, WA 98122, USA; Corresponding author
- Journal volume & issue
-
Vol. 3,
no. 1
p. 100074
Abstract
Summary: 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.
