Genetic evaluation of patients with non-syndromic male infertility

Abstract

Purpose: This review provides an update on the genetics of male infertility with emphasis on the current state of research, the genetic disorders that can lead to non-syndromic male infertility, and the genetic tests available for patients.

Methods: A comprehensive review of the scientific literature referenced in PubMed was conducted using keywords related to male infertility and genetics. The search included articles with English abstracts appearing online after 2000.

Results: Mutations in 31 distinct genes have been identified as a cause of non-syndromic human male infertility, and the number is increasing constantly. Screening gene panels by high-throughput sequencing can be offered to patients in order to identify genes involved in various forms of human non-syndromic infertility. We propose a workflow for genetic tests which takes into account semen alterations.

Conclusions: The identification and characterization of the genetic basis of male infertility have broad implications not only for understanding the cause of infertility but also in determining the prognosis, selection of treatment options, and management of couples. Genetic diagnosis is essential for the success of ART techniques and for preserving future fertility as well as the prognosis for testicular sperm extraction (TESE) and adopted therapeutics.

Keywords: Gene panel; Genetics; Male infertility; Non-syndromic; Whole exome sequencing.

Fig. 1

The workflow for genetic tests in male infertility. According to semen analysis, karyotype, Y chromosome microdeletion testing or specific gene mutation screening can be suggested to patients

Fig. 2

Examples of karyotype anomalies. a Klinefelter syndrome—47,XXY (adopted from www.qfg.com.au). b Reciprocal translocation involving chromosome 4 and 11 (adopted from http://what-when-how.com/genetics). c Karyotype in patient with Robertsonian translocation involving chromosome 13 and 14 (adopted from Răchișan et al. 2017 [17]). d Karyotype of a patient with inversion 9 (adopted from Jeong et al. 2010 [18])

Fig. 3

Y chromosome microdeletion testing. a Schematic diagram of human Y chromosome indicating the male-specific region of Y chromosome. AZFa-c: azoospermia factor a–c; PAR1 and PAR2: the pseudoautosomal regions. Genotype/phenotype relations of complete AZF deletions is given for each region. b Examples of multiplex PCRs recommended by European Academy of Andrology (EAA) and European Molecular Genetics Quality Network (EMQN) for the detection of Yq microdeletions. Two STS loci in each AZF region are analyzed and PCR products run on 3% agarose gel

Fig. 4

Candidate gene approach. The method involves identifying a cohort of patients with the same phenotype as in the model animal and sequencing the human homolog of the candidate gene in these patients

Fig. 5

Whole-genome approaches. a Single nucleotide polymorphism (SNP) arrays. SNP array technology is based on the discrimination between the two possible SNP alleles (A or B) for a specific position in the genome. The hypothesis is the whole region surrounding the mutation is identical in the group of patients with same phenotype; therefore, all the polymorphic markers, SNPs, of the area are homozygous and can be readily detected. Regions of homozygosity can be visualized by specific programs such as HomoSNP (adopted from Karampetsou et al. 2014 [37]). b Comparative genomic hybridization (CGH) arrays. The patient DNA and a normal control DNA, used as reference, are differentially labeled using fluorescent dyes. The two DNAs are then mixed together and hybridized on a microarray slide on which each spot represents a specific locus in the genome. The relative intensity between the two fluorescent dyes is calculated for each probe (adopted from Karampetsou et al. 2014 [37]). c High-throughput sequencing. High-throughput sequencing technologies enable researchers to perform massively parallel sequencing. In practice, it can be used for whole-genome (WGS) or whole-exome sequencing (WES); both create an enormous amount of raw data requiring complex bioinformatic analyses to extract useful information

Fig. 6

Cohorts of patients that can be involved in genetic studies for the quest of infertility genes. In the case of a cohort of genetically unrelated patients presenting an identical phenotype, a frequent mutation inherited from a common ancestor, known as a founder mutation, is searched for. Family-based studies provide an alternative approach to identify genes involved in infertility. The genetic etiology of a phenotype within a family has a high probability of being identical which allows a straightforward analysis