Review Article
A Systematic Review of Genetic Causes of Male Infertility Diagnosed by Whole-Exome Sequencing in the Pakistani Population: Updates from 2015 to June 2025
Issue:
Volume 13, Issue 4, December 2025
Pages:
73-82
Received:
26 August 2025
Accepted:
18 September 2025
Published:
10 October 2025
DOI:
10.11648/j.ijgg.20251304.11
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Abstract: Male infertility in Pakistan exhibits unique genetic patterns due to high consanguinity rates (65%). This systematic review of 38 studies (2015-2025) analyzed 2,041 participants (1,503 infertile men, 538 controls) using whole-exome sequencing (WES). Key findings reveal distinct genetic causes and inheritance patterns specific to this population. Chromosomal abnormalities affected 20.9% of azoospermic men, primarily Klinefelter syndrome (14.7%). Y-chromosome microdeletions occurred in 8% of cases, mostly in the AZFc region (50%). We identified 72 pathogenic variants across 58 genes, with 70.8% being novel to Pakistani populations. Consanguinity drove homozygous inheritance in 72.2% of cases. The most frequently mutated genes included ADAD2 (30% of non-obstructive azoospermia), HFM1 (20%), and DNAH family members (28.7% of motility defects). Variant types comprised frameshift (38.9%), missense (33.3%), nonsense (16.7%), and splicing mutations (11.1%). Significant biochemical markers included the CAT rs7943316 TT genotype (70.9% vs 14% controls) and elevated oxidative stress markers. These findings establish the first comprehensive genetic profile of Pakistani male infertility, demonstrating the profound impact of consanguinity on disease expression. The results emphasize the need for population-specific diagnostic protocols that prioritize DNAH/CFAP genes for motility disorders and ADAD2 for non-obstructive azoospermia. This review provides critical insights for genetic counseling and clinical management in high-consanguinity populations.
Abstract: Male infertility in Pakistan exhibits unique genetic patterns due to high consanguinity rates (65%). This systematic review of 38 studies (2015-2025) analyzed 2,041 participants (1,503 infertile men, 538 controls) using whole-exome sequencing (WES). Key findings reveal distinct genetic causes and inheritance patterns specific to this population. Ch...
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,
Nisar Ahmad,
Ahmad Faraz
