Diverse monogenic subforms of human spermatogenic failure

Area of Science:

• Genetics
• Reproductive Biology
• Genomic Medicine

Background:

• Non-obstructive azoospermia (NOA) is a severe form of male infertility with challenging genetic underpinnings.
• Current NOA classification relies on testis histology, not genetic factors.
• Identifying genetic causes is crucial for understanding and potentially treating NOA.

Purpose of the Study:

• To define the genetic basis of non-obstructive azoospermia (NOA).
• To identify novel genes and molecular subforms associated with NOA.
• To propose a genetics-based framework for classifying male infertility.

Main Methods:

• Whole exome sequencing of over 1000 NOA cases.
• Two-stage burden testing with 2072 NOA cases and 11,587 fertile controls.
• Integration with single-cell RNA sequencing data and mouse models.

Main Results:

• A plausible recessive Mendelian cause was identified in 20% of NOA cases.
• Support was found for 21 genes associated with NOA, many previously unlinked to Mendelian traits.
• NOA genes were grouped into molecular subforms based on synchronized expression patterns, including a novel subform linked to spermatogonial mitotic divisions.

Conclusions:

• NOA is an understudied Mendelian disorder with significant genetic heterogeneity.
• The study provides a framework for organizing male infertility genetics.
• Findings may lead to a rational, genetics-based classification of NOA and male infertility.