Genome-wide compound heterozygote analysis highlights DPY19L2 alleles in a non-consanguineous Spanish family with a complete form of globozoospermia

ABSTRACT

Research

question: Would the use of genome-wide genotyping be an advantageous strategy to identify the molecular aetiology of two brothers from a non-consanguineous family, clinically diagnosed with total globozoospermia?

Design

Two related Spanish globozoospermic patients were studied. Eight first- and second-degree family members were also included in the study. The clinical procedure included anamnesis, physical examination, and semen analyses. Acrosome visualization was performed by FITC-PSA labelling and ultrastructural TEM and SEM sperm analysis. Sperm DNA fragmentation was determined by TUNEL and SCD. Molecular analysis included: the detection of deletion of DPY19L2 gene by a BPa gap-PCR; and genotyping by using a high-throughput genome-wide genotyping platform and a genotype imputation strategy.

Results

The biological characteristics of the two globozoospermic siblings included round-shaped sperm head without acrosome; ultrastructural defects in sperm; increased sperm fragmentation and aneuploidies, inability of sperm to activate oocytes (correctable with artificial activation) and good developmental potential of IVF-ICSI generated embryos. Our genetic study focused on a genome-wide compound heterozygote analysis which identified two deleterious rare coding-variants in DPY19L2 gene [rs771726551 (c.431T>A exon3) and rs147579680 (c.869G>A exon8)].

Conclusion

Genome-wide compound heterozygote analysis strategy should be considered for molecular screening in globozoospermia and other rare congenital diseases, particularly in cases from non-consanguineous families.