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Background <p>Whole-genome sequencing (WGS) is an efficient, accurate, and high-throughput technique used for the discovery of exonic as well as non-exonic variants causing different genetic anomalies, improving clinical management for the disease. This study was designed to evaluate pathogenic genetic variants related to male infertility in male infertile families in remote rural areas of Pakistan.</p> Methods <p>For the five families recruited, WGS was conducted on 14 patients and 6healthy controls. WGS was performed using the Illumina TruSeq DNA Nano Library Prep workflow protocol. DNA was assessed with TapeStation and sequenced using the TruSeq kit (Illumina). Bioinformatics tools were then used to identify potential causative variants, including indels and single-nucleotide variants.</p> Results <p>In family 1, five homozygous nonsynonymous SNVs were identified in <i>FMR1</i>, <i>PHF8</i>, <i>TOPBP1</i>, and <i>DAB2IP</i>. These X-linked or recessive variants cause amino acid changes that affect key cellular pathways. In family 10, homozygous nonsynonymous SNVs were detected in <i>FOS</i>,<i> MIR452</i>,<i> PDHA1</i>,<i> and SERPINB1</i>, implicating roles in structural, transcriptional, metabolic, and synaptic processes. In family 11, a frameshift deletion in <i>PRDM9</i> and nonsynonymous SNVs in <i>KIAA1210</i>, suggesting possible disruption of gene regulation and protein stability. In family 13, multiple nonsynonymous variants were identified in <i>SPATA20</i>,<i> and G6PD</i>,, with implications in reproductive function, angiogenesis, enzymatic activity, and neuromuscular disorders. SNV Variant was detected in <i>SLC12A4</i> in Family 15.</p> Conclusion <p>The study contributes to a systematic understanding of the problem and provides a basis for identifying causal variations in idiopathic cases of male infertility, setting targets for future therapeutic development.</p>

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Whole genome sequencing approach for the detection of rare protein-altering variants associated with familial male infertility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月31日

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  • Muhammad Ajmal,
  • Muhammad Riaz Khan,
  • Arvand Akbari,
  • Helen Castillo-Madeen,
  • Jasvinder S. Ahuja,
  • Taqweem Ul Haq,
  • Donald F. Conrad,
  • Aftab Ali Shah

摘要

Background

Whole-genome sequencing (WGS) is an efficient, accurate, and high-throughput technique used for the discovery of exonic as well as non-exonic variants causing different genetic anomalies, improving clinical management for the disease. This study was designed to evaluate pathogenic genetic variants related to male infertility in male infertile families in remote rural areas of Pakistan.

Methods

For the five families recruited, WGS was conducted on 14 patients and 6healthy controls. WGS was performed using the Illumina TruSeq DNA Nano Library Prep workflow protocol. DNA was assessed with TapeStation and sequenced using the TruSeq kit (Illumina). Bioinformatics tools were then used to identify potential causative variants, including indels and single-nucleotide variants.

Results

In family 1, five homozygous nonsynonymous SNVs were identified in FMR1, PHF8, TOPBP1, and DAB2IP. These X-linked or recessive variants cause amino acid changes that affect key cellular pathways. In family 10, homozygous nonsynonymous SNVs were detected in FOS, MIR452, PDHA1, and SERPINB1, implicating roles in structural, transcriptional, metabolic, and synaptic processes. In family 11, a frameshift deletion in PRDM9 and nonsynonymous SNVs in KIAA1210, suggesting possible disruption of gene regulation and protein stability. In family 13, multiple nonsynonymous variants were identified in SPATA20, and G6PD,, with implications in reproductive function, angiogenesis, enzymatic activity, and neuromuscular disorders. SNV Variant was detected in SLC12A4 in Family 15.

Conclusion

The study contributes to a systematic understanding of the problem and provides a basis for identifying causal variations in idiopathic cases of male infertility, setting targets for future therapeutic development.