Sateesh Maddirevula1, Saud Alsahli1, Lamees Alhabeeb1, Nisha Patel1, Fatema Alzahrani1, Hanan E Shamseldin1, Shams Anazi1, Nour Ewida1, Hessa S Alsaif1, Jawahir Y Mohamed1, Anas M Alazami1, Niema Ibrahim1, Firdous Abdulwahab1, Mais Hashem1, Mohamed Abouelhoda1,2, Dorota Monies1,2, Nada Al Tassan1,2, Muneera Alshammari3, Afaf Alsagheir4, Mohammed Zain Seidahmed5, Samira Sogati6, Mona S Aglan7, Muddathir H Hamad3, Mustafa A Salih3, Ahlam A Hamed8, Nadia Alhashmi9, Amira Nabil10, Fatima Alfadli11, Ghada M H Abdel-Salam7, Hisham Alkuraya12, Winnie Ong Peitee13, W T Keng13, Abdullah Qasem14, Aziza M Mushiba15, Maha S Zaki7, Mahmoud R Fassad16, Majid Alfadhel17, Saji Alexander18, Yasser Sabr19, Samia Temtamy7, Alka V Ekbote20, Samira Ismail7, Gamal Ahmed Hosny21, Ghada A Otaify7, Khalda Amr7, Saeed Al Tala22, Arif O Khan1,23, Tamer Rizk24, Aida Alaqeel14, Abdulmonem Alsiddiky25, Ankur Singh26, Seema Kapoor27, Amal Alhashem14,28, Eissa Faqeih15, Ranad Shaheen29, Fowzan S Alkuraya30,31,32,33. 1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 2. Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. 3. Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 4. Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 5. Pediatric Department, Forces Hospital, Riyadh, Saudi Arabia. 6. Department of Medical Genetics, King Fahad General Hospital, Jeddah, Saudi Arabia. 7. Clinical Genetics Department, Human Genetics & Genome Research Division, Center of Excellence of Human Genetics, National Research Centre, Cairo, Egypt. 8. Department of Pediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan. 9. Department of Pediatrics, Royal Hospital, Muscat, Oman. 10. Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt. 11. Department of Pediatrics, Maternity and Children's Hospital, Medina, Saudi Arabia. 12. Global Eye Care, Specialized Medical Center Hospital, Riyadh, Saudi Arabia. 13. Clinical Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia. 14. Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia. 15. Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia. 16. The Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt. 17. 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. 18. Department of Paediatric Endocrinology and Diabetes, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. 19. Department of Obstetrics and Gynecology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 20. Clinical Genetics Unit, Christian Medical College, Vellore, India. 21. Department of Orthopedic Surgery, Banha University, Banha, Egypt. 22. Department of Pediatrics, Armed Forces Hospital Program Southwest Region, Khamis Mushait, Saudi Arabia. 23. Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates. 24. Department of Pediatric Neurology, Dr. Sulaiman Al Habib Hospital, Riyadh, Saudi Arabia. 25. Department of Orthopedics, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 26. Department of Pediatrics, Genetic Clinic, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. 27. Department of Pediatrics, Maulana Azad Medical College, New Delhi, India. 28. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 29. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. rshaheen@kfshrc.edu.sa. 30. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa. 31. Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa. 32. Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa. 33. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
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.
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.
Authors: Eva González-Iglesias; Ana López-Vázquez; Susana Noval; María Nieves-Moreno; María Granados-Fernández; Natalia Arruti; Irene Rosa-Pérez; Marta Pacio-Míguez; Victoria E F Montaño; Patricia Rodríguez-Solana; Angela Del Pozo; Fernando Santos-Simarro; Elena Vallespín Journal: Int J Mol Sci Date: 2022-04-11 Impact factor: 6.208
Authors: Eman Ahmed El-Attar; Rasha Mohamed Helmy Elkaffas; Sarah Ahmed Aglan; Iman S Naga; Amira Nabil; Hoda Y Abdallah Journal: Front Genet Date: 2022-05-13 Impact factor: 4.772
Authors: Mallory J Owen; Sebastien Lefebvre; Christian Hansen; Chris M Kunard; David P Dimmock; Laurie D Smith; Gunter Scharer; Rebecca Mardach; Mary J Willis; Annette Feigenbaum; Anna-Kaisa Niemi; Yan Ding; Luca Van Der Kraan; Katarzyna Ellsworth; Lucia Guidugli; Bryan R Lajoie; Timothy K McPhail; Shyamal S Mehtalia; Kevin K Chau; Yong H Kwon; Zhanyang Zhu; Sergey Batalov; Shimul Chowdhury; Seema Rego; James Perry; Mark Speziale; Mark Nespeca; Meredith S Wright; Martin G Reese; Francisco M De La Vega; Joe Azure; Erwin Frise; Charlene Son Rigby; Sandy White; Charlotte A Hobbs; Sheldon Gilmer; Gail Knight; Albert Oriol; Jerica Lenberg; Shareef A Nahas; Kate Perofsky; Kyu Kim; Jeanne Carroll; Nicole G Coufal; Erica Sanford; Kristen Wigby; Jacqueline Weir; Vicki S Thomson; Louise Fraser; Seka S Lazare; Yoon H Shin; Haiying Grunenwald; Richard Lee; David Jones; Duke Tran; Andrew Gross; Patrick Daigle; Anne Case; Marisa Lue; James A Richardson; John Reynders; Thomas Defay; Kevin P Hall; Narayanan Veeraraghavan; Stephen F Kingsmore Journal: Nat Commun Date: 2022-07-26 Impact factor: 17.694