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Background <p>Genetic defects account for a substantial proportion of severe male infertility, yet standard diagnostic methods such as karyotyping and multiplex PCR for Y-chromosomal microdeletions fail to detect all clinically relevant abnormalities.</p> Methods <p>We investigated 51 rigorously pre-selected men with confirmed non-obstructive azoospermia (NOA), all presenting with normal karyotype or balanced chromosomal rearrangement, negative Y-microdeletion PCR results, no <i>CFTR</i> mutations, and no recognized environmental, infectious, endocrine, or metabolic causes of spermatogenic failure. Genome-wide CNV detection was performed using Agilent GenetiSure Cyto 4 × 180&#xa0;K array CGH (GRCh38).</p> Results <p>Clinically relevant CNVs were identified in 6/51 men (11.8%). Pathogenic variants included one autosomal duplication (5q11.1–q11.2; 5.79&#xa0;Mb) encompassing testis-expressed genes DDX4, MCIDAS, and CCNO, and three Y-chromosomal deletions affecting AZFc gene families. Two patients exhibited partial AZFc deletions, and one a smaller deletion restricted to GOLGA2P2Y, all three not detected by routine PCR. Three variants of uncertain significance, were detected in two men, both with recurrent deletion on chromosome 15q11.1–q11.2 (GOLGA gene family) and one with additional duplication on chromosome 8p11 (POTEA gen).</p> Conclusions <p>These findings demonstrate the diagnostic value of array CGH in idiopathic NOA, particularly for identifying atypical or partial AZFc deletions not detectable by PCR-based screening. Autosomal CNVs affecting testis-expressed or germ-cell-relevant genes may also contribute to spermatogenic failure. Incorporation of CNV-based genomic testing into diagnostic algorithms could improve diagnostic yield in genetically unexplained NOA.</p>

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Genome-wide copy-number analysis improves detection of pathogenic AZFc and autosomal variants in idiopathic non-obstructive azoospermia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • Andreja Zagorac,
  • Nejc Kozar,
  • Boris Zagradišnik,
  • Milan Reljič,
  • Nadja Kokalj Vokač

摘要

Background

Genetic defects account for a substantial proportion of severe male infertility, yet standard diagnostic methods such as karyotyping and multiplex PCR for Y-chromosomal microdeletions fail to detect all clinically relevant abnormalities.

Methods

We investigated 51 rigorously pre-selected men with confirmed non-obstructive azoospermia (NOA), all presenting with normal karyotype or balanced chromosomal rearrangement, negative Y-microdeletion PCR results, no CFTR mutations, and no recognized environmental, infectious, endocrine, or metabolic causes of spermatogenic failure. Genome-wide CNV detection was performed using Agilent GenetiSure Cyto 4 × 180 K array CGH (GRCh38).

Results

Clinically relevant CNVs were identified in 6/51 men (11.8%). Pathogenic variants included one autosomal duplication (5q11.1–q11.2; 5.79 Mb) encompassing testis-expressed genes DDX4, MCIDAS, and CCNO, and three Y-chromosomal deletions affecting AZFc gene families. Two patients exhibited partial AZFc deletions, and one a smaller deletion restricted to GOLGA2P2Y, all three not detected by routine PCR. Three variants of uncertain significance, were detected in two men, both with recurrent deletion on chromosome 15q11.1–q11.2 (GOLGA gene family) and one with additional duplication on chromosome 8p11 (POTEA gen).

Conclusions

These findings demonstrate the diagnostic value of array CGH in idiopathic NOA, particularly for identifying atypical or partial AZFc deletions not detectable by PCR-based screening. Autosomal CNVs affecting testis-expressed or germ-cell-relevant genes may also contribute to spermatogenic failure. Incorporation of CNV-based genomic testing into diagnostic algorithms could improve diagnostic yield in genetically unexplained NOA.