Genomic testing for copy number and single nucleotide variants in spermatogenic failure

Area of Science:

• Genetics
• Reproductive Biology
• Genomic Medicine

Background:

• Male infertility, specifically spermatogenic failure (SPGF), affects a significant portion of the population.
• The genetic underpinnings of unexplained SPGF remain incompletely understood, necessitating advanced diagnostic tools.
• Conventional genetic testing methods have limitations in detecting the full spectrum of genomic alterations.

Purpose of the Study:

• To identify clinically significant genomic copy number variants (CNVs) and single nucleotide variants (SNVs) in males with unexplained SPGF.
• To evaluate the diagnostic yield of a combined array comparative genomic hybridization (aCGH) and whole-exome sequencing (WES) approach for male infertility.
• To compare the detection rate of genomic aberrations with conventional genetic testing methods.

Main Methods:

• Peripheral blood DNA from 97 participants with oligozoospermia, severe oligozoospermia, or non-obstructive azoospermia (NOA) was analyzed.
• Copy number variants (CNVs) were assessed using array comparative genomic hybridization (aCGH).
• Single nucleotide variants (SNVs) and indels were identified through whole-exome sequencing (WES).

Main Results:

• Clinically relevant genomic aberrations were detected in approximately 29% of patients.
• Specific diagnostic CNVs, including deletions in TEX11, DDX53, and STK11, were identified in NOA patients.
• Whole-exome sequencing (WES) identified significant SNVs and/or indels in 9% of patients, including variants in AR, KAL1, and NR0B1.

Conclusions:

• A combined aCGH/WES strategy identified pathogenic SNVs and CNVs in 15% of patients with unexplained SPGF.
• This genomic approach offers a higher detection rate compared to conventional testing for aneuploidies and Y chromosome microdeletions.
• Comprehensive genomic analysis is crucial for the emerging diagnostic landscape of male infertility and complex genetic conditions.