Identification of a DPY19L2 Mutation Linking Globozoospermia to Congenital Heart Defects in a Consanguineous Family: A Genetic Analysis

Abstract

Background

Male infertility is a complex condition with significant genetic heterogeneity. Globozoospermia, a rare form of teratozoospermia characterized by round-headed sperm, is frequently associated with mutations in the DPY19L2 gene. While the link between DPY19L2 and infertility is established, the co-occurrence of male infertility and congenital heart defects (CHDs) in offspring within consanguineous families highlights the necessity of investigating compounded genetic risks and independent segregation of recessive traits.

Methods

We recruited a consanguineous family comprising a male proband with infertility and a history of adverse reproductive outcomes, including an offspring with transposition of the great arteries (TGA). Semen analysis was performed according to WHO guidelines (2010, 5th Edition). Genetic investigation included karyotyping and whole-exome sequencing (WES) for the proband, his spouse, and family members. Sanger sequencing was used to validate identified variants.

Results

Semen analysis of the proband revealed 100% round-headed sperm (globozoospermia) with normal volume and density but reduced motility. WES identified a homozygous mutation in the DPY19L2 gene (c.63dupG; p.Arg22Alafs ^∗66). This mutation was also confirmed in the proband’s affected brother. Pedigree analysis suggested an autosomal recessive inheritance pattern resulting from consanguinity. The specific mutation explains the fertilization failure in previous intracytoplasmic sperm injection (ICSI) cycles and highlights the necessity for artificial oocyte activation (AOA).

Conclusion

This study confirms the pathogenic role of the DPY19L2 c.63dupG mutation in familial globozoospermia. Furthermore, it highlights the critical importance of comprehensive genetic screening in consanguineous couples presenting with infertility and congenital anomalies. Early genetic diagnosis can guide appropriate assisted reproductive strategies, such as ICSI with AOA, and inform risk assessment for future pregnancies.