From Bench to Bedside: Uncovering Genetic Causes of Severe Male Infertility and Implementing Diagnostic Strategies
Caroline Cazin
Centro de Investigación del Cáncer. Universidad de Salamanca - CSIC
Infertility affects approximately 1 in 8 couples, with male factors implicated in over 50% of cases, making male infertility a significant public health issue. This condition is characterized by diverse phenotypes, including abnormalities in sperm morphology and number, often linked to genetic causes. While it is estimated that around 4,000 genes are involved in human spermatogenesis, only a limited number have been studied in detail. The objective of this research is to identify new genetic factors contributing to severe male infertility, thereby enhancing the accuracy of genetic diagnoses.
Using Whole Exome Sequencing (WES) on infertile patients, multiple genetic abnormalities linked to specific sperm defects were identified. These findings were further validated through the use of CRISPR/Cas9 technology to generate corresponding genetic variations in mouse models, allowing the functional study of candidate genes. This work led to the discovery of numerous monogenic causes of infertility, affecting phenotypes such as non-obstructive azoospermia (NOA), acephalic spermatozoa syndrome (ASS), macrozoospermia, and multiple morphological abnormalities of the flagella (MMAF). Additionally, novel genes involved in human spermatogenesis were identified, improving the diagnostic yield for certain patients. For example, in a cohort of 96 patients with NOA, 22 genes were found to be involved in the phenotype, with genetic variants in 23% of cases, including 7 genes for which no anomalies had been previously reported in humans. This approach doubled the efficiency of diagnosis compared to traditional methods.
Overall, this research has expanded the understanding of the genetic basis of male infertility, leading to more precise diagnoses and potentially better management options
for affected individuals.