Autosomal single-gene disorders involved in human infertility

Abstract

Human infertility, defined as the inability to conceive after 1 year of unprotected intercourse, is a healthcare problem that has a worldwide impact. Genetic causes of human infertility are manifold. In addition to the chromosomal aneuploidies and rearrangements, single-gene defects can interfere with human fertility. This paper provides a review of the most common autosomal recessive and autosomal dominant single-gene disorders involved in human infertility. The genes reviewed are ,, ,, ,, ,, and genes. These genes may be expressed throughout the hypothalamic-pituitary-gonadal-outflow tract axis, and the phenotype of affected individuals varies considerably from varying degrees of spermatogenic dysfunction leading to various degrees of reduced sperm parameters, through hypogonadotropic hypogonadism reslting in pubertal deficiencies, until gonadal dysgenesis and XY and XX sex reversal. Furthermore, congenital bilateral absence of the vas deferens, as well as premature ovarian failure, have been reported to be associated with some single-gene defects.

Genes predisposing to syndromic and nonsyndromic infertility: a narrative review

“…A missense heterozygous mutation involving c. 3G → A transition and two heterozygous frameshift mutations named c. 666delC and c. 390delG were reported [17]. The following were also reported: p. Pro311Leu, p. Arg191Cys, p. Gly121Ser, p. Asp238Asn, and p. Gly123Ala/p.…”

“…A heterozygous deletion called 643delA, and a heterozygous genetic change known as T657C was identified among Iranian women with recurrent pregnancy losses [17].…”

“…Causes early meiotic arrest, disrupting the spermatogenic process in males [17], resulting in spermatogenic failure 4 (SPGF4), a disorder characterized by azoospermia. In females, early meiotic arrest Table 2 Genes predisposing to nonsyndromic spermatogenic failure and sperm morphological abnormalities (Continued)…”

The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility—A Unifying Hypothesis?

“…These mutations are generally autosomal recessive and inherited from fertile parents in homozygous, compound heterozygous or hemizygous form. However, autosomal dominant monogenic mutations can also precipitate a state of infertility including SYCP3 (Synaptonemal complex protein 3), NR5A1 (nuclear receptor subfamily 5 group A member 1) and the WT1 (Wilms' tumor 1) gene (68). A recent detailed analysis of the genetic causes of non-obstructive azoospermia (NOA) concluded that the largest single category of monogenic defects detected in NOA patients comprises genes involved in different stages of spermatogenesis, mostly functioning in the prophase of the first meiotic division as well as transcriptional and endocrine regulators of reproduction (67).…”

Clinical Evaluation of a Custom Gene Panel as a Tool for Precision Male Infertility Diagnosis by Next-Generation Sequencing

“…In fact, long been known chromosomal syndromes associated with infertility diagnosed by karyotype analysis, but only in recent years studies have been conducted on specific chromosomal regions and identified single genes linked to infertility problems. About 30% of infertility cases are still apparently sine causa and it is difficult for these to be syndromic conditions, but rather for conditions in which the reproductive defect is the only diagnostic indication [ 25 , 26 ]. Knowledge of the molecular defect attributable to single genes could lead to the development of targeted therapies to correct the genetic defect.…”