Exploring Familial Hypospadias: Genetic Insights from Copy Number Variants in a Quad Family
Sourabh Kumar1, Jyoti Sharma2, Dinesh Gupta3, Rahila Sardar4, Preeti Lal4, Vishesh Jain5, Anjan Kumar Dhua5, Devendra Kumar Yadav5, Sandeep Agarwala5, Monis Bilal Shamsi6, Hamdi Hameed Almaramhy7, Harpreet Singh8, Neeta Kumar9, Prabudh Goel5*
¹Project Research Scientist I, Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India.
²Project Research Scientist II, Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India.
³Group Leader, Translational Bioinformatics, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
⁴Vgenomics, India.
⁵Professor of Paediatric Surgery, Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India.
⁶Centre for Genetics and Inherited Diseases (CGID), Taibah University, Madinah 42361, Saudi Arabia; Department of Basic Medical Sciences, College of Medicine, Taibah University, Madinah 42361, Saudi Arabia.
⁷College of Medicine, Taibah University, Medina, Saudi Arabia.
⁸Scientist F and Programme Officer, Division of Development Research, Indian Council of Medical Research, New Delhi, India.
⁹Scientist, Division of Discovery Research, Indian Council of Medical Research, New Delhi, India.
*Corresponding Author: Prabudh Goel, Professor of Paediatric Surgery, Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India, PIN 110029
https://doi.org/10.58624/SVOAPD.2026.05.015
Received: April 24, 2026
Published: June 16, 2026
Citation: Kumar S, Sharma J, Gupta D, Sardar R, Lal P, Jain V, Dhua AK, Yadav DK, Agarwala S, Shamsi MB, Almaramhy HH, Singh H, Kumar N, Goel P. Exploring Familial Hypospadias: Genetic Insights from Copy Number Variants in a Quad Family. SVOA Paediatrics 2026, 5:3, 101-114. doi: 10.58624/ SVOAPD.2026.05.015
Abstract
Background: The genetic aetiology of hypospadias is likely to be oligogenic with possible interactions between multiple genetic variants and contributory environmental factors. A pathogenic copy number variant (CNV) is usually harboured by 3-14% of patients with rare developmental disorders. With this background, a landscape of CNVs in a family with multiple affected and unaffected progeny is presented with an investigation into the potentially responsible, molecular pathways underlying the etiopathogenesis of hypospadias. The family consists of both parents, two sons with hypospadias, and two unaffected sons (whole exome data unavailable for one unaffected son). CNVkit pipeline was executed and the structural variant files were annotated. The identified CNVs were studied for distribution within the family, inheritance, gene-composition and correlated with available information for potential relevance to the phenotype.
Results: Cumulative analysis (F:father, M:mother, P1-P2:affected progeny, U:unaffected progeny) identified 152 unique CNVs[size:1.49 kb–6.53 Mb) comprising 139 deletions and 13 duplications. P1 and P2 were represented by 29/52 and 22/50 de novo CNVs, respectively. P1 & P2 have 16 common deletion CNVs:8/16 CNVs are absent in U (inherited:6, de novo:2); de novo CNVs: chr6:29100942:29306930:DEL & chr16:11379821:11441076:DEL. de novo CNVs encompass OR2J1 and OR14J1 genes expressed in testis and spermatozoa as major histocompatibility complex (MHC)-linked olfactory receptors. CNVs encompassing GREM1, RRN3, KIAA0753 and HNF1B genes relevant to hypospadias were identified.
Conclusion: The landscape of CNVs in familial hypospadias has been presented to enhance the understanding of their distribution, frequency and impact on the development of hypospadias and a database has been generated for future research.
Keywords: Hypospadias, Whole Exome Sequencing, Copy Number Variants, Single Nucleotide Polymorphisms, OR2J1, OR14J1, GREM1, HNF1B, KIAA0753, RRN3