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

doi:10.1016/j.xhgg.2021.100074

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

HGG Adv. 2021 Dec 3;3(1):100074. doi: 10.1016/j.xhgg.2021.100074. eCollection 2022 Jan 13.

Authors

Chaofan Zhang¹, Angad Jolly^{1

2}, Brian J Shayota^{1

3}, Juliana F Mazzeu^{4

5}, Haowei Du¹, Moez Dawood^{1

2

6}, Patricia Celestino Soper⁷, Ariadne Ramalho de Lima⁴, Bárbara Merfort Ferreira⁴, Zeynep Coban-Akdemir^{1

8}, Janson White¹, Deborah Shears⁹, Fraser Robert Thomson¹⁰, Sarah Louise Douglas¹¹, Andrew Wainwright⁹, Kathryn Bailey¹², Paul Wordsworth¹³, Mike Oldridge¹⁴, Tracy Lester¹⁴, Alistair D Calder¹⁵, Katja Dumic¹⁶, Siddharth Banka^{17

18}, Dian Donnai¹⁸, Shalini N Jhangiani⁶, Lorraine Potocki^{1

3}, Wendy K Chung¹⁹, Sara Mora⁷, Hope Northrup²⁰, Myla Ashfaq²⁰, Jill A Rosenfeld¹, Kati Mason^{7

21}, Lynda C Pollack²¹, Allyn McConkie-Rosell²², Wei Kelly²², Marie McDonald²², Natalie S Hauser²³, Peter Leahy²⁴, Cynthia M Powell²⁵, Raquel Boy²⁶, Rachel Sayuri Honjo²⁷, Fernando Kok²⁸, Lucia R Martelli²⁹, Vicente Odone Filho³⁰, Genomics England Research Consortium³¹, Donna M Muzny⁶, Richard A Gibbs^{1

6}, Jennifer E Posey¹, Pengfei Liu^{1

32}, James R Lupski^{1

3

6

33}, V Reid Sutton^{1

3}, Claudia M B Carvalho^{1

34}

Affiliations

¹ Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
² Medical Scientist Training Program, BCM, Houston, TX 77030, USA.
³ Texas Children's Hospital, Houston, TX 77030, USA.
⁴ University of Brasilia, Brasilia 70050, Brazil.
⁵ Robinow Syndrome Foundation, Anoka, MN 55303, USA.
⁶ Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
⁷ GeneDx Inc., Gaithersburg, MD 20878, USA.
⁸ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, UTHealth, Houston, TX 77030, USA.
⁹ Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK.
¹⁰ Cardiothoracic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK.
¹¹ NHS Lothian, Edinburgh EH1 3EG, UK.
¹² Pediatric Rheumatology, Nuffield Orthopedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK.
¹³ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Oxford OX3 7LD, UK.
¹⁴ Oxford Regional Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK.
¹⁵ Radiology Department, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
¹⁶ Department of Pediatric Endocrinology and Diabetes, University Clinical Center Zagreb, Zagreb 10000, Croatia.
¹⁷ Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK.
¹⁸ Manchester Center for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
¹⁹ Department of Pediatrics and Medicine, Columbia University, NY 10032, USA.
²⁰ 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.
²¹ Arnold Palmer Hospital for Children, Orlando, FL 32806, USA.
²² Division of Medical Genetics, Duke University Medical Center, Durham, NC 27708, USA.
²³ Medical Genetics, Inova Fairfax Hospital, Falls Church, VA 22042, USA.
²⁴ Cook Children's Hospital, Fort Worth, TX 76104, USA.
²⁵ Division of Pediatric Genetics and Metabolism, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
²⁶ State University of Rio de Janeiro, Rio de Janeiro 21941, Brazil.
²⁷ Unidade de Genética, Instituto da Criança - Hospital das Clinicas HCFMUSP, Faculdade de Medicina, University of Sao Paulo, São Paulo 05508, Brasil.
²⁸ Mendelics Análise Genômica, São Paulo 04013, Brasil.
²⁹ Department of Genetics, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo 05508, Brazil.
³⁰ Instituto de Tratamento do Câncer Infantil, São Paulo University Medical School, Hospital Israelita Albert Einstein, São Paulo 05508, Brasil.
³¹ Genomics England and William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK.
³² Baylor Genetics, Houston, TX 77021, USA.
³³ Department of Pediatrics, BCM, Houston, TX 77030, USA.
³⁴ Pacific Northwest Research Institute (PNRI), Seattle, WA 98122, USA.

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.

Keywords: DVL2; HPO terms; genotype-phenotype correlation; indel mutations; molecular diagnosis; quantitative phenotyping cluster heatmap; screw-tail breed dogs; skeletal dysplasia; traits and OMIM clinical synopsis.

Associated data

figshare/10.6084/m9.figshare.4530893.v7

Abstract

Associated data

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