Publication Details

Title :

Expanding the phenome and variome of skeletal dysplasia.


Genetics in Medicine

Impact Factor:



Maddirevula S1, Alsahli S1, Alhabeeb L1, Patel N1, Alzahrani F1, Shamseldin HE1, Anazi S1, Ewida N1, Alsaif HS1, Mohamed JY1, Alazami AM1, Ibrahim N1, Abdulwahab F1, Hashem M1, Abouelhoda M1,2, Monies D1,2, Al Tassan N1,2, Alshammari M3, Alsagheir A4, Seidahmed MZ5, Sogati S6, Aglan MS7, Hamad MH3, Salih MA3, Hamed AA8, Alhashmi N9, Nabil A10, Alfadli F11, Abdel-Salam GMH7, Alkuraya H12, Peitee WO13, Keng WT13, Qasem A14, Mushiba AM15, Zaki MS7, Fassad MR16, Alfadhel M17, Alexander S18, Sabr Y19, Temtamy S7, Ekbote AV20, Ismail S7, Hosny GA21, Otaify GA7, Amr K7, Al Tala S22, Khan AO1,23, Rizk T24, Alaqeel A14, Alsiddiky A25, Singh A26, Kapoor S27, Alhashem A14,28, Faqeih E15, Shaheen R1, Alkuraya FS1,2,14,28.


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, Security 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.

Year of Publication:





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.