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Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia

European Journal of Human Genetics volume 33, pages 607–613 (2025)Cite this article

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Abstract

Skeletal dysplasias are a clinically and genetically heterogeneous group of rare disorders. Studies from large cohorts are essential to provide insights into the disease epidemiology, phenotypic spectrum, and mutational profiles. Here we enumerate additional 248 Indians from 197 families with a skeletal dysplasia, following a similar study earlier. We achieved a clinical-molecular diagnosis in 145 families by targeted analysis in 37 and next generation sequencing (exomes and genomes) in 108 families that resulted in a diagnostic yield of 73.6% (145 of 197 families). We identified 149 causal variants, of which 85 were novel, across 73 genes. Eighty-one distinct monogenic forms of skeletal dysplasia were observed with a high proportion of autosomal recessive skeletal dysplasias (60%, 84 families). We observed consanguinity in 35% of the families. Lysosomal storage diseases with skeletal involvement, FGFR3-related skeletal dysplasia and disorders of bone mineralisation were most frequent in this cohort. We expand the phenotypic and genotypic spectrum of rarely reported conditions (RAB33B, TRIP11, NEPRO, RPL13, COL27A1, PTHR1, EXOC6B, PRKACA, FUZ and RSPRY1) and noted novel gene-disease relationships for PISD, BNIP1, TONSL, CCN2 and SCUBE3 related skeletal dysplasia. We successfully implemented genomic testing for skeletal dysplasia in clinical and research settings. Our study provides valuable information on the spectrum of skeletal dysplasia and disease-causing variants for Asian Indians.

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Fig. 1: Flow chart outlining our study design for evaluation of skeletal dysplasia.

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Most of the data relevant to this study are included here. However, any additional information about the study is available from the corresponding authors upon reasonable request.

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Acknowledgements

We would like to thank the participants and their families for their consent and participation in the study. We are grateful to all the referring physicians who made this work possible. We thank the “SG10K_Pilot Investigators” for providing the SG10K_Pilot data (EGAD00001005337). The data from the “SG10K_Pilot Study” reported here were obtained from EGA. This manuscript was not prepared in collaboration with the “SG10K_Pilot Study” and does not necessarily reflect the opinions or views of the “SG10K_Pilot Study”. Additionally, we acknowledge that Figure 1 was created using BioRender.

Funding

This work was supported by the following research projects awarded to Katta M Girisha: Department of Biotechnology/Wellcome Trust India Alliance project titled “Centre for Rare Disease Diagnosis, Research and Training” (Reference number: IA/CRC/20/1/600002), Department of Science and Technology, Government of India project entitled ‘Application of Autozygosity Mapping and Exome Sequencing to Identify Genetic Basis of Disorders of Skeletal Development’ (SB/SO/HS/005/2014), and Indian Council of Medical Research project entitled “Clinical and molecular evaluation of inherited arthropathies and multiple vertebral segmentation defects” (Project ID: BMS 54/2/2013). Ashwin Dalal is supported by the Department of Biotechnology, Government of India project entitled ‘Development of Genomic Technologies for Predictive Genetic Health and Forensic Profiling’ (Grant No. BTI/AAQ/01/CDFD-Flagship/2019). Swati Singh is supported by Joint CSIR-UGC NET Junior Research Fellowship awarded by Human Resource Development Group under Council of Scientific and Industrial Research (CSIR), Government of India: (08/028(0002)/2019-EMR-I).

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Author notes

  1. These authors contributed equally: Prince Jacob, Swati Singh

Authors and Affiliations

  1. Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

    Prince Jacob, Swati Singh, Gandham SriLakshmi Bhavani, Dhanya Lakshmi Narayanan, Anju Shukla & Katta M. Girisha

  2. Department of Medical Genetics, Apollo Children’s Hospitals, Chennai, India

    Kalpana Gowrishankar

  3. Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Kochi, India

    Sheela Nampoothiri

  4. Division of Medical Genetics, Mazumdar Shaw Medical Center, Narayana Hrudayalaya Hospitals, Bangalore, India

    S. J. Patil

  5. Department of Pediatrics, Dr. S.N. Medical College, Jodhpur, India

    J. P. Soni

  6. Genetic Clinic, Department of Pediatrics, Seth GS Medical College and King Edward Memorial Hospital, Parel, Mumbai, India

    Mamta Muranjan

  7. Department of Medical Genetics, Maulana Azad Medical College and Lok Nayak hospital, New Delhi, India

    Seema Kapoor

  8. Department of Pediatrics, All India Institute of Medical Sciences, Bhopal, India

    Bhavna Dhingra

  9. Department of Pediatrics, Aarupadai Veedu Medical College and Hospital, Vinayaka Mission’s Research Foundation-DU, Kirumampakkam, Pondicherry, India

    Ballambattu Vishnu Bhat

  10. The Purple Gene Clinic, Mumbai, India

    Shruti Bajaj

  11. Department of Pediatrics, All India Institute of Medical Sciences, Patna, India

    Amrita Banerjee

  12. Rheumatology, Jagadguru Sri Shivarathreeshwara (JSS) Medical College, Mysore, India

    Mahabaleshwar Mamadapur

  13. Genetics Clinic, Department of Pediatrics, SAT Hospital, Government Medical College, Thiruvananthapuram, Kerala, India

    Sankar V. Hariharan

  14. Department of Paediatrics, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India

    Nutan Kamath

  15. Department of Pediatrics, K. S. Hegde Medical Academy, NITTE University, Deralakatte, Mangalore, India

    Rathika D. Shenoy

  16. Department of Clinical Medicine, American University of Antigua, Antigua, Antigua and Barbuda

    Rathika D. Shenoy

  17. Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

    Deepti Suri

  18. Diagnostics Division, Centre for DNA Fingerprinting & Diagnostics, Hyderabad, India

    Ashwin Dalal

  19. Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

    Shubha R. Phadke

  20. Department of Radiology, Musashino-Yowakai Hospital, Tokyo, Japan

    Gen Nishimura

  21. Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium

    Geert Mortier

  22. Department of Pediatric Orthopedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

    Hitesh Shah

  23. Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University Muscat, Muscat, Oman

    Katta M. Girisha

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  1. Prince Jacob
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  2. Swati Singh
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  3. Gandham SriLakshmi Bhavani
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  25. Hitesh Shah
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Contributions

Conceptualisation: KMG, HS, GSB; Data curation: PJ, SS, GSB; Formal analysis: PJ, SS, GSB, KMG; Funding acquisition: KMG, AD; Investigation: PJ, SS GSB, GN, GM, HS, KMG; Resources: KG, DLN, SN, SJP, JPS, MM, SK, BD, BSB, VB, SB, AB, MM, SVH, NK., RDS, DS, AS, SRP; Supervision: GSB, HS, KMG; Writing original draft: PJ, SS, KMG; Writing final draft: PJ, SS, GSB, KG, DLN, SN, SJP, JPS, MM, SK, BD, BVB, SB, AB, MM, SVH, NK, RDS, DS, AS, AD, SRP, GN, GM, HS, KMG All authors have read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Hitesh Shah or Katta M. Girisha.

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Competing interests

KMG is the director of Suma Genomics Private Limited and holds shares of the company that has interests in genetic testing.

Ethical approval

We obtained the informed consents from the families for genetic testing, publication of data and clinical photographs. This study has the approvals from the Institutional Ethics Committee at the Kasturba Medical College and Kasturba Hospital, Manipal (IEC:921/2018; IEC:363/2020, IEC: 430/2013, IEC: 570/2015, IEC: 302/2013).

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Jacob, P., Singh, S., Bhavani, G.S. et al. Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia. Eur J Hum Genet 33, 607–613 (2025). https://doi.org/10.1038/s41431-024-01776-8

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