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

• Published in: Reproductive biomedicine online Vol. 45; no. 2; pp. 332 - 340
• Main Authors: López-Rodrigo, Olga, Bossini-Castillo, Lara, Carmona, F. David, Bassas, Lluís, Larriba, Sara
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.08.2022
• Subjects: Genetic diagnosis; Genome-wide association studies; Globozoospermia; GWAS; Male infertility; Non-consanguinity; Sperm ultrastructure; Non-consanguinity; Genome-wide association studies; GWAS; Male infertility; Globozoospermia; Sperm ultrastructure; Genetic diagnosis
• ISSN: 1472-6483; 1472-6491
• DOI: 10.1016/j.rbmo.2022.03.035

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? 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 fluorescein isothiocyanate–Pisum sativum agglutinin labelling and ultrastructural electron microscope sperm analysis. Sperm DNA fragmentation was determined by TUNEL and SCD. Molecular analysis included: the detection of deletion of the DPY19L2 gene by a BPa (break point "a") gap-polymerase chain reaction, and genotyping by using a high-throughput genome-wide genotyping platform and a genotype imputation strategy. The biological characteristics of the two globozoospermic siblings included round-headed spermatozoa without an acrosome; ultrastructural defects in spermatozoa; increased sperm fragmentation and aneuploidies, inability of spermatozoa to activate oocytes (correctable with artificial activation) and good developmental potential of embryos generated by IVF/intracytoplasmic sperm injection. This genetic study focused on a genome-wide compound heterozygote analysis that identified two deleterious rare coding variants in the DPY19L2 gene [rs771726551 (c.431T>A exon 3) and rs147579680 (c.869G>A exon 8)]. A 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.