Infertility: genetic causes

What’s infertility?

Following the Wolrd Health Organization (WHO) definition, infertility is a “a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse.”

Whether infertility should be considered a disease should probably be a question of sensitivity and perception of each patient, as reproductive desires are not equal for all and, for many people, being able or not to reproduce may simply be little relevant to their choices of life. Said this, it’s important that infertile couples can get access to diagnostic procedures and assisted reproductive technology (ART) when they are seeking a baby.

It is estimated that infertility affects 10-15% of couples.

Sterility is different from infertility, as it refers to couples where one or both partners are affected by an irreversible or untreatable condition which will make impossible for them to have children at all.

Primary and secondary infertility

Primary infertility: always according to WHO, primary infertility would affect women whose pregnancy spontaneously miscarries or whose pregnancy ends in a still born child, without ever having had a healthy baby. Precise causes may be found, sometimes later in the diagnostic process, also for primary infertility (balanced translocations, for instance, may lead to multiple, consecutive miscarriages for a long time before having a baby).

Secondary infertility, always according to WHO, may be defined in women who experience miscarriages or inability to get pregnant after already having had a baby.

Nongenetic causes of infertility: females

We discuss below the main nongenetic causes of infertility:

A) Tube defects: Fallopian tubes are blocked or damaged. This may hamper the sperm progress into the egg or, by contrast, the egg descent. Tube damage is often caused by neglected sexual infections (e.g. Chlamydia).

B) Ovulatory endocrine infertility: ovaries do not produce eggs due to hormonal deficiencies.

C) Endometriosis: this is the ectopic growth and functioning of endometrial-like tissue (the tissue that covers the inside of the uterus) in places other than the uterus. This may result in pain and infertility as it can cause adhesions to ovaries and Fallopian tubes.

D) Dimished ovarian reserve (DOR): ovaries contain just few eggs. Diminished ovarian reserve may be congenital or acquired, even due to medical or surgical procedures, although it’s a completely normal process in female ageing. DOR is sometimes referred to as POR (Poor Ovarian Reserve).

E) Multiple causes

Nongenetic causes of infertility: males

Here below the most frequent, nongenetic causes of male infertility:

A) Varicocele: this is the varicose dilation of the pampiniform plexus of veins within the scrotum. It leads to scrotum increased temperature. As spermatogenesis is extremely sensitive to temperature, the increase of even just one degree can lead to a significant loss in sperm production. Unfortunately, varicocele may be recurrent and appear again even after surgical repair. However, because varicocele contributes significantly to male reproductive pathology, varicocele correction is an important option, being more cost-effective than both intrauterine insemination and in vitro fertilization.

B) Cryptorchidism (undescended testicle): it is defined as the missing or incomplete descent of one or both testicles in the scrotum. Cryptorchidism is a congenital condition, often found in male patients affected by genetic syndromes, and is usually associated with male sterility.

C) Infections: chronic infections may lead to partial or total closure of the vas deferens, which connects the epididymis (a small reservoir where spermatozoa are collected) to the urethra. If vas deferens get closed, spermatozoa cannot reach the penis and cannot be ejaculated. A frequent cause of congenital absence of the vas deferens is actually genetic (see below).

D) Hormonal deficiencies: as sperm production is regulated by hormones, some hormonal deficiency (hypogonadism) may lead to male infertility or sterility. Abuse of testosterone as doping agent mal also causes infertility, as it suppresses natural testosterone production. For hypogonadal males on exogenous testosterone (taken from outside), therapy can begin with cessation of the exogenous testosterone and administration of human chorionic gonadotropin and an oral follicle-stimulating hormone (FSH).

E) Immunological factors: spermatozoa get attacked by male auto-antibodies or by female antibodies.

F) Surgery and diabetes: some urological surgery and neurogenic impotence due to diabetes may lead to retrograde ejaculation.

Genetic causes of infertility: females

Genetic causes of infertility may be chromosomal or genic. Balanced translocations, for instance, and other chromosomal rearrangements may cause primary or secondary infertility in females as well as in males. Genic causes, which are actually rarer than the chromosomal ones, are consistent with point mutations in genes involved in oocytes (eggs) production and/or their genetic content.

Most frequent genetic causes to be considered in infertile females include the following: Turner syndrome (entire or mosaic monosomy X, which is usually associated with streak gonads), congenital adrenal hyperplasia (CAH, due to by 21-hydroxylase deficiency caused by CYP21A2 gene mutations, or, more rarely, due to 11-beta-hydroxylase deficiency caused by CYP11B1 gene mutations, or 3-beta-hydroxysteroid dehydrogenase type 2 deficiency caused by HSD3B2 gene mutations), renal cysts and diabetes syndrome (HNF1B mutations), Mayer-Rokitansky-Kuster-Hauser syndrome (congenital absence or hypoplasia of the vagina and the uterus, which affects approximately 1 in 5,000 newborn girls, no gene known so far), mullerian duct aplasia, unilateral renal aplasia, and cervicothoracic somite dysplasia (MURCS, also known as Mayer-Rokitansky-Kuster-Hauser syndrome type II, no gene known so far), androgen insensitivity (cause by AR gene mutations), gondal dysgenesis (females with a 46,XY karyotype who may have a SRY gene mutation or simply streak gonads of unknown origin), premature ovarian failure (POF, caused by mutation in one of several different genes) and hypogonadotrophic hypogonadism, which may be caused by mutations in one of several different genes as well.

So, including the aforementioned conditions, a multigene panel to look for genic causes of female may reasonably include the following genes: AR, BMP15, BNC1, C11orf80, CYP21A2, DHEAST, DIAPH2, ERCC6, FANCM, FANCL, FIGLA, FMR1, FOXL2, FSHR, GDF9, HFM1, HSF2BP, LHB, LHCGR, MCMDC1, MCM8, MEI1, MSH4, MSH5, NOBOX, NR5A1, POF1B, PSMC3IP, REC114, SHBG, SPAG17, SRD5A1, SRD5A2, STAG3, STX2, SYCE1, TUBB8, WEE2, XRCC2.

Hypogonadotropic hypogonadism may not be considered in first place for genetic screening, as such condition is more easily identified by hormonal dosages. However, at present, the series of genes included in the pathogenesis of hypogonadotropic hypogonadism include the following: ANOS1, CHD7, DUSP6, FEZF1, FGF17, FGF8, FGFR1, FLRT3, FMR1, FSHB, GNRH1, GNRHR, HS6ST1, IL17RD, KISS1, KISS1R, LHB, NDNF, NELF, PROK2, PROKR2, SEMA3A, SPRY4, TAC3, TACR3, WDR11.

Genetic causes of infertility: males

Also for males, genetic causes of infertility may be chromosomal or genic. Balanced translocations, for instance, and other chromosomal rearrangements may cause primary or secondary infertility in males (as well as in females, as said above). Genic causes, which are actually rarer than chromosomal causes, are consistent with point mutations in genes involved in sperm production and/or their genetic content.

Most frequent genetic causes of male infertility include the following: congenital (bilateral) absence of vas deferens (CBAVD or CAVD, which is caused in otherwise asymptomatic men by two mutations in the cystic fibrosis gene: one severe or mild mutation plus the 5T allele), Klinefelter syndrome (entire or mosaic 47,XXY karyotype), Y chromosome microdeletions involving the AZF regions, isodicentric Y chromosome, Y chromosome inversions (which may be associated to both normal and reduced fertility), males with a 46,XX karyotype (hiding translocations or mosaicism involving portions of the Y chromosome), primary ciliary dyskinesia and, again, hypogonadotropic hypogonadism.

In practice, a panel to screen for genic causes of male infertility may be composed of the following genes, which also include causes of meiotic arrest: AR, AZF, CATSPER1, CFTR, DEFB126, DEFB128, DNAH17, MAATS1, FSHR, LHCGR, MSH4, MSH5, SYCP2, TTC29, XRCC2.

As said for genetic causes of female infertility, the screening for hypogonadotropic hypogonadism may not be considered at first, as hormonal imbalances are easily detected by blood tests. When signs of hypogonadotropic hypogonadism are detected at blood testing, a multigene panel for hypogonadotropic hypogonadism is highly recommended.

General approach in genetic testing for female and male infertility

As the genetic causes of female and male infertility are most commonly chromosomal (just balanced translocations have a global frequency of 1 in 1,000 persons), the standard approach in genetic testing of infertile couples is usually limited to karyotype analysis. Karyotype analysis warrants a good detection rate at a very reasonable cost. However, when karyotype is normal, deeper genetic screening may be recommended, taking into account that some of the aforementioned genic causes of infertility may be totally asymptomatic except for infertility. Genic causes may be tested by next generation sequencing. For example, our panels may be performed based on whole exome or whole genome sequencing. To see our updated panels for female and male infertility, please see our list of panels here.

Whole exome/genome sequencing for male and female infertility?

So, to which extent is whole exome or whole genome sequencing useful to look for genetic causes of male and female infertility?

Karyotype analysis warrants unveiling the most common causes of genetic infertility, which are chromosomal rearrangements. So, karyotype analysis (alongside with CFTR testing in azoospermic males) may be considered a good and, in most cases, sufficient approach. Furthermore, we must say that several ART procedures (including sperm and egg donation) may successfully overcome several cases of couple infertility, independently from the underlying cause.

So, why should a doctor consider doing whole exome or whole genome sequencing (or multigene panel testing) in infertile couples with a normal karyotype?

Actually, whole exome sequencing or whole genome sequencing may come to hand in infertile couples mostly for a couple of reasons (and maybe one more):

  1. unveiling possible, rare causes of sterility (permanent impossibility to conceive), which may definitively guide to the best ART procedure or suggest long-term couple choices.
  2. treating silent or paucisymptomatic genetic conditions which, apart from infertility, may be underdiagnosed. For instance, patients with hypogonadotropic hypogonadism may take advantage of hormonal replacement therapy. Hypogonadotropic hypogonadism may be diagnosed based on hormonal dosages and requires multigene panel testing or whole exome sequencing to be genetically confirmed.
  3. unveiling the status of healthy carrier for some genetic disorders. The general reproductive risk (i.e. the risk of having a baby affected by a congenital disease or syndrome at birth) is about 3%. Due to the multitude of rare diseases and the largely unknown clinical significance of most genetic variants, the general reproductive risk cannot be significantly reduced by pre-conceptional genetic screenings. However, because whole exome/genome sequencing may identify the healthy carrier status for some genetic disorder, while the general reproductive risk can never be set to zero, the specific reproductive risk for those isolated conditions can be precisely calculated and prenatal testing can be planned.

Idiopathic causes of male and female infertility

Still in a not neglectable percentage of cases, the causes of couple infertility remain unknown. This is called idiopathic infertility. It is likely that many of these cases will be solved in the future thanks to new medical and scientific acquisitions. Nevertheless, even couples affected by idiopathic infertility may benefit from ART procedures and eventually be successful in having a pregnancy and a healthy baby.

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World Health Organization:

Istituto Superiore di Sanità:

NCBI PubMed: PMID: 26806078, PMID: 28675168, PMID: 27132576, PMID: 20301513.

Clinical Genetics and Genomics, 2nd ed, Oxford Desk Reference, p.722 and p.750.

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