Familial DMRT1-related non-obstructive azoospermia: a case report

Area of Science:

• Genetics
• Reproductive Medicine
• Urology

Background:

• Non-obstructive azoospermia (NOA) and varicocele are significant causes of male infertility.
• Genetic factors are increasingly recognized in the etiology of NOA.
• Understanding transmission patterns of genetic causes of infertility is crucial for genetic counseling and treatment.

Purpose of the Study:

• To document an unprecedented case of father-to-son transmission of genetically determined NOA and varicocele.
• To investigate the genetic basis of azoospermia in a familial context.
• To explore the implications for male infertility diagnosis and assisted reproductive technologies.

Main Methods:

• Clinical evaluation of a father and son diagnosed with NOA and varicocele.
• Genetic counseling and comprehensive genetic analyses in the son, including karyotype, Y chromosome microdeletions, CFTR screening, next-generation sequencing (NGS) infertility panels, and array comparative genomic hybridization (array-CGH).
• Comparison of genetic findings between father and son to identify inherited factors.

Main Results:

• Array-CGH identified a 224-283 kb deletion (del9p24.3) in the son, inherited from the father.
• The deletion encompassed parts of the KANK1 and DMRT1 genes.
• Haploinsufficiency of the DMRT1 gene due to loss of function was identified as the likely cause of azoospermia.

Conclusions:

• This case confirms father-to-son transmission of a DMRT1-including deletion, providing critical insights for clinicians managing male infertility.
• The findings suggest that genetic deletions, even in cases of complete azoospermia, may offer hope and warrant reconsideration of assisted reproductive technology (ART) inclusion criteria.
• Further research is needed to clarify the specific role of DMRT1 alterations in varicocele development, as varicocele may have influenced the phenotype in this case.