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Expanding the phenome and variome of skeletal dysplasia

Maddirevula S 1 , Alsahli S 1 , Alhabeeb L 1 , Patel N 1 , Alzahrani F 1 , Shamseldin HE 1 Show all authors , Anazi S 1 , Ewida N 1 , Alsaif HS 1 , Mohamed JY 1 , Alazami AM 1 , Ibrahim N 1 , Abdulwahab F 1 , Hashem M 1 , Abouelhoda M 1 , Monies D 1 , Al Tassan N 1 , Alshammari M 2 , Alsagheir A 3 , Seidahmed MZ 4 , Sogati S 5 , Aglan MS 6 , Hamad MH 2 , Salih MA 2 , Hamed AA 7 , Alhashmi N 8 , Nabil A 9 , Alfadli F 10 , Abdel-Salam GMH 6 , Alkuraya H 11 , Peitee WO 12 , Keng WT 12 , Qasem A 13 , Mushiba AM 14 , Zaki MS 6 , Fassad MR 15 , Alfadhel M 16 , Alexander S 17 , Sabr Y 18 , Temtamy S 6 , Ekbote AV 19 , Ismail S 6 , Hosny GA 20 , Otaify GA 6 , Amr K 6 , Al Tala S 21 , Khan AO 1 , Rizk T 22 , Alaqeel A 13 , Alsiddiky A 23 , Singh A 24 , Kapoor S 25 , Alhashem A 13 , Faqeih E 14 , Shaheen R 26 , Alkuraya FS 27

Affiliations 

  • 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  • 2 Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  • 3 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  • 4 Pediatric Department, Forces Hospital, Riyadh, Saudi Arabia
  • 5 Department of Medical Genetics, King Fahad General Hospital, Jeddah, Saudi Arabia
  • 6 Clinical Genetics Department, Human Genetics & Genome Research Division, Center of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
  • 7 Department of Pediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
  • 8 Department of Pediatrics, Royal Hospital, Muscat, Oman
  • 9 Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
  • 10 Department of Pediatrics, Maternity and Children's Hospital, Medina, Saudi Arabia
  • 11 Global Eye Care, Specialized Medical Center Hospital, Riyadh, Saudi Arabia
  • 12 Clinical Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
  • 13 Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia
  • 14 Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
  • 15 The Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
  • 16 King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Genetics Division, Department of Pediatrics, King Abdulaziz Medical City, MNGHA, Riyadh, Saudi Arabia
  • 17 Department of Paediatric Endocrinology and Diabetes, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
  • 18 Department of Obstetrics and Gynecology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  • 19 Clinical Genetics Unit, Christian Medical College, Vellore, India
  • 20 Department of Orthopedic Surgery, Banha University, Banha, Egypt
  • 21 Department of Pediatrics, Armed Forces Hospital Program Southwest Region, Khamis Mushait, Saudi Arabia
  • 22 Department of Pediatric Neurology, Dr. Sulaiman Al Habib Hospital, Riyadh, Saudi Arabia
  • 23 Department of Orthopedics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  • 24 Department of Pediatrics, Genetic Clinic, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
  • 25 Department of Pediatrics, Maulana Azad Medical College, New Delhi, India
  • 26 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. rshaheen@kfshrc.edu.sa
  • 27 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa
Genet Med, 2018 12;20(12):1609-1616.
PMID: 29620724 DOI: 10.1038/gim.2018.50

Abstract

PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.

METHODS: Detailed phenotyping and next-generation sequencing (panel and exome).

RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average.

CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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