High resolution X chromosome-specific array-CGH detects new CNVs in infertile males

Area of Science:

• Genetics
• Reproductive Biology
• Human Genomics

Background:

• The role of X-linked copy number variations (CNVs) in male infertility remains largely undefined, despite the X chromosome's enrichment in spermatogenesis genes.
• Previous research has primarily focused on Y-chromosome CNVs, leaving X-linked factors under-investigated.

Purpose of the Study:

• To investigate the impact of X-linked genetic factors on male infertility by applying high-resolution X chromosome-specific array comparative genomic hybridization (array-CGH).
• To identify clinically relevant CNVs associated with spermatogenic impairment in a cohort of infertile men.

Main Methods:

• High-resolution X chromosome-specific array-CGH was performed on 199 men with varying sperm counts.
• Patient-specific deletions were analyzed in large cohorts of cases and normozoospermic controls.

Main Results:

• Identified 73 CNVs, including 55 novel ones, constituting the largest collection of X-linked CNVs related to spermatogenesis.
• Discovered 12 patient-specific deletions with potential clinical significance, with Cancer Testis Antigen genes being the most frequently affected.
• Observed a significantly higher global burden of deletions in patients (0.57 deletions/person) compared to controls (0.21 deletions/person), with a greater mean sequence loss per person.

Conclusions:

• A significant deletion burden on the X chromosome is associated with spermatogenic impairment.
• No highly recurrent deletions were found on the X chromosome, but several patient-specific CNVs and candidate spermatogenesis genes were identified.
• These findings highlight novel genetic targets for future research into male infertility and spermatogenesis.