Improved phenotypic classification of male infertility to promote discovery of genetic causes

Abstract

An increasing number of genes are being described in the context of non-syndromic male infertility. Linking the underlying genetic causes of non-syndromic male infertility with clinical data from patients is important to establish new genotype-phenotype correlations. This process can be facilitated by using universal nomenclature, but no standardized vocabulary is available in the field of non-syndromic male infertility. The International Male Infertility Genomics Consortium aimed at filling this gap, providing a standardized vocabulary containing nomenclature based on the Human Phenotype Ontology (HPO). The "HPO tree" was substantially revised compared with the previous version and is based on the clinical work-up of infertile men, including physical examination and hormonal assessment. Some causes of male infertility can already be suspected based on the patient's clinical history, whereas in other instances, a testicular biopsy is needed for diagnosis. We assembled 49 HPO terms that are linked in a logical hierarchy and showed examples of morphological features of spermatozoa and testicular histology of infertile men with identified genetic diagnoses to describe the phenotypes. This work will help to record patients' phenotypes systematically and facilitate communication between geneticists and andrologists. Collaboration across institutions will improve the identification of patients with the same phenotypes, which will promote the discovery of novel genetic causes for non-syndromic male infertility.

Figure 1.. The novel HPO tree.

Overview of the HPO terms in the context of non-syndromic male infertility. The starting point for our work is the term “Decreased male fertility” with all further terms sprouting from here. Of these, 34 phenotypes can be diagnosed by semen analysis, 11 by testicular biopsy, and the two terms “Gonadal dysgenesis” and “Hypogonadotropic hypogonadism” can by suspected based on the patient’s history and confirmed by clinical work-up. As these terms represent syndromic conditions, they were not followed-up further. MMAF = multiple morphological abnormalities of the sperm flagella; SCO = Sertoli cell-only; CBAVD = congenital bilateral absence of the vas deferens. *These terms were not followed-up further in our analysis

Figure 2.. Selected HPO terms and associated semen and testicular phenotypes.

Overview of selected examples of HPO terms and the corresponding schematic phenotypes. Additional HPO terms, for example, branching from “Abnormal sperm morphology”, are not depicted here. Abnormal sperm morphology can be a cause of abnormal sperm motility. SCO: Sertoli cell-only

Figure 3.. Spermatogenic phenotypes of men with aberrant sperm morphology.

A. Sperm sample of a patient diagnosed with multiple morphological abnormalities of the sperm flagella (MMAF) caused by variants in DNAH1 (ID M3398 from the Male Reproductive Genomics [MERGE] cohort). B. Sperm sample of a patient (M3253) with globozoospermia; in this patient, a homozygous deletion of the complete DPY19L2 gene was identified as the cause for infertility. C. Sperm sample of a patient (M3100) with a homozygous frameshift variant in AURKC, which caused macrozoospermia, with large irregular heads and multiple flagella per sperm. (Figures provided by Christoph Brenker, unpublished work).

Figure 4.. Broad spectrum of testicular phenotypes observed in histology samples from infertile men with a genetic diagnoses.

A: man (M3254) is shown (magnification in B). C: Tubular shadows found in a patient (M1317) with a heterozygous —likely pathogenic— DMRT1 variant (magnification in D). E: Sertoli cell-only phenotype observed in a patient (M364) with a heterozygous loss-of-function variant in TRIM71 (magnification in F). G Spermatocyte arrest observed in a patient (M2408) with a homozygous pathogenic variant in ADAD2 (magnification in H). I: Round spermatid arrest in a patient (M1938) with a homozygous pathogenic variant in SPO11 (magnification in J). K: Hypospermatogenesis was diagnosed in a patient (M1843) with a chromosomal translocation (45,XY,der(13;14)(q10;q10)) (magnification in L). For all panels, human testicular tissue was stained with Periodic Acid Schiff (PAS). Cell types are labelled in the magnified images. (M.J.W., S.K., and F.T., unpublished work) SPG = spermatogonia; SPC = spermatocyte; RS = round spermatid; ES = elongating spermatid; TS = tubular shadows; SC = Sertoli cell.