A systematic review and standardized clinical validity assessment of male infertility genes

Abstract

Study question Which genes are confidently linked to human male infertility? Summary answer Our systematic literature search and clinical validity assessment reveals that a total of 67 genes are currently confidently linked to 81 human male infertility phenotypes. What is known already The discovery of novel male infertility genes is rapidly accelerating with the availability of Next-Generation Sequencing methods, but the quality of evidence for gene-disease relationships varies greatly. In order to improve genetic research, diagnostics and counseling, there is a need for an evidence-based overview of the currently known genes. Study design, size, duration We performed a systematic literature search and evidence assessment for all publications in Pubmed until June 2018 covering genetic causes of male infertility and/or defective male genitourinary development. Participants/materials, setting, methods Two independent reviewers conducted the literature search and included papers on the monogenic causes of human male infertility and excluded papers on genetic association or risk factors, karyotype anomalies and/or copy number variations affecting multiple genes. Next, the quality and the extent of all evidence supporting selected genes was weighed by a standardized scoring method and used to determine the clinical validity of each gene-disease relationship as expressed by the following six categories: no evidence, limited, moderate, strong, definitive or unable to classify. Main results and the role of chance From a total of 23,031 records, we included 1,286 publications about monogenic causes of male infertility leading to a list of 471 gene-disease relationships. The clinical validity of these gene-disease relationships varied widely and ranged from definitive (n=36) to strong (n=12), moderate (n=33), limited (n=86) or no evidence (n=154). A total of 150 gene-disease relationships could not be classified. Limitations, reasons for caution Our literature search was limited to Pubmed. Wider implications of the findings The comprehensive overview will aid researchers and clinicians in the field to establish gene lists for diagnostic screening using validated gene-disease criteria and identify gaps in our knowledge of male infertility. For future studies, the authors discuss the relevant and important international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Study funding/competing interest(s) This work was supported by a VICI grant from The Netherlands Organisation for Scientific Research (918-15-667 to JAV).

Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

“…We chose to report the heterozygous variant c.7118G>A in TEX15 , despite it being predicted as benign, because it was found in combination with another heterozygous variant (c.9223G>A ClinVar SCV000987204.1), predicted as deleterious (Table ). Moreover, TEX15 has moderate evidence of association with male infertility (Oud et al ., ). Hence, we report a potentially compound heterozygous patient (M1804) (Fig.…”

“…Initially, we analyzed the WES data for the three genes NR5A1 , DMRT1 , and TEX11 from our unstructured assessment (Tüttelmann et al ., ). Subsequently, we selected a set of genes based on a systematic review that established the clinical validity of candidate genes related to male infertility (Oud et al ., ). We considered all genes with definitive, strong, moderate, and limited evidence of monogenetic association with male infertility and selected those leading to the phenotypes presented by our patients, such as NOA, SCO, and germ cell maturation arrest (see Table S1).…”

“…As such, this approach can help identify novel genetic factors in different complex diseases, including male infertility (Krausz & Riera‐Escamilla, ). In fact, whole exome sequencing (WES) has already been employed to identify novel genes related to the phenotype of non‐obstructive azoospermia in humans (Gershoni et al ., ; Fakhro et al ., ), but the number of genes that can be confidently linked to this condition is still low (Oud et al ., ). Without stronger evidence, some findings may lead to distorted conclusions, resulting in inappropriate subsequent research or false understanding of genetic pathways (Oud et al ., ).…”

“…Regarding genes that do fulfill multiple levels of evidence for an association with male infertility, an unstructured assessment reportedly found three: NR5A1 , DMRT1 , and TEX11 (Tüttelmann et al ., ). Very recently, an extensive literature review and structured clinical validity assessment of a large number of genes showed that only a few have ‘strong’ evidence of being associated with male infertility, while many more have ‘moderate’ or ‘limited’ evidence (Oud et al ., ).…”

Fatty acids, food groups and semen variables in men referring to an Italian Fertility Clinic: Cross‐sectional analysis of a prospective cohort study

“…Genetic, epigenetic or physiological characteristics, or acute events, may cause infertility (Craig, Jenkins, Carrell, & Hotaling, ; Leaver, ; Oud et al, ). However, frequently impaired spermatogenesis has no clear explanation since it may be caused by chronic environmental exposures that are difficult to identify (Gabrielsen & Tanrikut, ).…”