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Exome Sequencing Leads to Diagnosis for 12 Percent of Infertile Men in Estonian Study

NEW YORK – Using an exome sequencing and targeted gene analysis approach, an international team led by investigators in Estonia reached genetic diagnoses in 12 percent of a cohort of male infertility cases.

The findings prompted Tartu University Hospital's Andrology Clinic to include clinical gene panel sequencing in its testing workup for male infertility patients, according to Maris Laan and Margus Punab, researchers at the university and hospital. In an email, they noted that "[t]o our knowledge, this broad availability of gene panel-based testing to infertility patients is rather unique in the world."

"The gene panel is constantly updated with the expanding list of new infertility genes," they added, noting that the resulting genetic diagnoses can help guide patient management and the assessment of genetic comorbidity.

The approach stems from an exome sequencing study of 521 infertile men that Laan, Punab, and colleagues from Estonia, the US, Belgium, Spain, and Italy reported in the American Journal of Human Genetics on Friday.

The participants included men with non-obstructive azoospermia or a complete lack of sperm production; reduced sperm counts, called oligozoospermia; and with male infertility related to a form of congenital testicular maldevelopment known as cryptorchidism. All were enrolled in the "Estonian Andrology" (ESTAND) cohort.

The exome analysis focused on 638 genes. When the team compared the sequences of the participants to those of 323 fertile men with normal sperm production, or "normzoospermia," it was able to diagnose 12 percent of the infertility cases, including 17 percent of patients with primary cryptorchidism, 11 percent with azoospermia, and 10 percent of oligozoospermia patients.

"We observed a spectrum of genetic defects — autosomal dominant conditions often affecting testis development and reproductive hormones, autosomal recessive infertility frequently linked to defective spermatogenesis, as well as X- and Y-chromosomal gene defects," Laan and Punab noted.

In that respect, they explained, results in the "outbred" Estonian population contrast with autosomal recessive forms of male infertility described in previous studies in consanguineous populations marked by marriage between members of the same extended family.

All told, the search led to 64 pathogenic or likely pathogenic variants in 39 candidate causal genes, including 19 recurrent alterations or those previously identified in infertile men. Two of the genes contained pathogenic or likely pathogenic variants across all three forms of male infertility, along with variants implicated in other health conditions ranging from anosmia (a full or partial loss of smell) to sleep disorders to delayed puberty.

The team noted that pathogenic or likely pathogenic variants were overrepresented in genes from the hypothalamic-pituitary-gonadal axis pathway. In additional, a subset of participants carried suspicious variants consistent with the presence of reproductive system-impacting congenital conditions.

In accordance with investigators' phenotypic assessments, which pointed to potential comorbidities in several infertility cases, they saw higher-than-usual rates of early cancer in participants with genetic forms of infertility. Moreover, at least half a dozen participants carried multiple likely pathogenic or pathogenic variants in the set of genes analyzed.

Together, the results pointed to the "added value of advanced genetic testing in a substantial fraction of infertile men," Laan and Punab concluded, noting that a significant subset of the genetic suspects identified were "not only relevant to infertility but also explaining other health conditions in the patient."