36 CLINICAL FOCUS
36 CLINICAL FOCUS
13 FEBRUARY 2026 ausdoc. com. au
Therapy Update
Genetics and the infertile couple
Fertility
Dr David Molloy is a gynaecologist and fertility specialist, and director of medical affairs at Queensland Fertility Group Brisbane, Virtus Health, Queensland.
Erin Anderson is a genetic counsellor in Spring Hill, Queensland.
A guide to the multiple genetic factors contributing to infertility and the options available to treat those with a fertility problem.
UNDERSTANDING the many genetic influences that affect human reproduction is important in the investigation and counselling of patients with reproductive issues. This article aims to present a guide for GPs to assist in the management of the infertile couple who, in this context, is considered a heterosexual couple who meet the clinical definitions of subfertility.
Couples-based fertility workup
It is essential that both members of a couple are considered as patients. For both individuals, a reproductive genetic medical history should include general personal medical history, family medical history( including any known genetic conditions), pregnancy and miscarriage history, and enquires about the health of any existing children.
For the female partner, the specific history to review includes genetically influenced reproductive conditions, such as endometriosis and polycystic ovarian syndrome. For the male partner, this includes assessment of any structural reproductive disorders such as maldescent of the testes, and chronic respiratory illness. The latter can be indicative of atypical cystic fibrosis or heterozygous CFTR carrier status, which can be associated with congenital absence of the vas deferens.
Clinical examination of the couple includes general body habitus, height and weight. A pelvic examination is indicated for the female partner, as well as pelvic ultrasound with reference to ovarian size and antral follicle count. Semen analysis is warranted for the male and, if this is significantly abnormal, testicular examination or referral to a fertility specialist should be considered.
Pregnancy and miscarriage history is an important aspect in the family histories for both individuals, as recurrent miscarriage can indicate an underlying genetic cause such as a balanced chromosome translocation.
Investigation of genetic issues related to fertility
Blood tests include anti-Müllerian hormone( AMH) for the woman, and chromosome karyotype for both parties. Research within the authors’ fertility unit shows that 2-3 % of couples with either primary or secondary infertility have a chromosomal anomaly such as an aneuploidy or translocation. The incidence is greater in patients with recurrent IVF failure and, if not performed previously, dual karyotype is imperative. While more esoteric genetic conditions such as XX- or XY-gonadal dysgenesis are rare, these will be identified by routine karyotype.
If the semen analysis demonstrates azoospermia, Y chromosome microdeletion( ie, DAZ gene family) testing should be ordered.
Genetic factors in female fertility
Multiple genes play important roles in the production and maturation of oocytes in women. The X chromosome is vital for reproduction. Various X chromosomal abnormalities— including monosomy X( Turner syndrome) or triple X syndrome; duplications, deletions, inversions or Xq isochromosome and unbalanced or balanced X; autosome translocations or rearrangements— can lead to premature ovarian insufficiency( POI).
POI may manifest from birth with streak ovaries, or present later with delayed or absent adolescence, or premature menopause( before age 40).
Fragile X syndrome, due to CGG repeat expansions in the FMR1 gene on the X chromosome, is the leading cause of inherited intellectual impairment. Women who carry a‘ premutation’ are at risk of having a child with fragile X syndrome( with variable and attenuated symptoms in female children due to X inactivation). There are also implications for the health of the woman. Depending on the repeat size, premutation carriers are at risk of POI, fragile X-associated tremor / ataxia syndrome( FXTAS) and an increased risk of learning challenges or mood disorders. The severity of fragile X syndrome and premutation carrier health complications is not directly correlated with the number of CGG repeats. Since approximately 1 in 250 women( and 1 in 800 men) are carriers of a fragile X premutation, genetic counselling for patients is recommended.
Age-related fertility decline and chromosomal abnormalities Defects in oocyte meiosis and chromosome segregation may underlie various fertility issues, particularly in older patients. More than 60 % of oocytes in women over 40 have chromosomal abnormalities, with rates increasing significantly with advancing maternal age. 1, 2 Aneuploidy rates exceeding 90 % are common in embryos created with oocytes from patents older than 43 years. 3, 4 Male fertility also decreases with age, due to reduced semen volume and quality, and a significant increase in sperm DNA fragmentation.
To address the increasing aneuploidy rates with increasing age, IVF units often recommend preimplantation genetic testing for aneuploidy( PGT-A) for women 35 years and older. 1, 5 Use of PGT-A in this subgroup to transfer only euploid embryos may lead to higher pregnancy rates per embryo transfer, and decreased miscarriage or medical termination rates. However, aneuploidy is only a part of the fertility challenges associated with aging oocytes. Reduced mitochondrial function and mutations in DNA repair genes are also thought to contribute to poor outcomes for older patients.
Diminished ovarian reserve, PCOS and endometriosis Approximately 10 % of patients who present to an IVF clinic will have diminished ovarian reserve as evidenced by a low AMH and / or decreased antral follicle count. 6 This condition significantly impacts IVF success rates, necessitating careful counselling for affected patients.
For younger women diagnosed with diminished ovarian reserve who do not have immediate pregnancy plans, oocyte cryopreservation should be discussed as a potential fertility preservation option.
Polycystic ovary syndrome( PCOS) is a complex endocrine disorder with multifactorial aetiology, involving both genetic and environmental components. The strong heritable basis of PCOS underscores the importance of obtaining a comprehensive first-degree family history during patient assessment. Variations in genes, microRNAs and non-coding RNAs associated with hormone regulation, insulin sensitivity and follicular development can all contribute to the development of PCOS.
Endometriosis is a prevalent condition among IVF patients and may affect 25-50 % of women seeking fertility treatment. 7, 8 The familial clustering of endometriosis is significant, with first-degree relatives having a five to sevenfold increased risk of developing the condition compared to the general population. 9, 10 This again highlights the importance of family history, and of counselling women about early diagnosis and long-term surveillance of the condition.
Genetic factors in male infertility
Male infertility accounts for about one-third of presentations to IVF units, emphasising the importance of considering the male partner in fertility evaluations. 11 While environmental and lifestyle factors are certainly contributory to sperm quality, underlying genetic issues are implicated in up to 30 % of
12, 13 male infertility cases.
Azoospermia( absence of sperm in the ejaculate) may be obstructive or non-obstructive. Investigation into the underlying cause is required. Obstructive azoospermia may be due to congenital absence of the vas deferens or other congenital obstructions, cystic fibrosis, or Young syndrome( a rare genetic condition associated with sinusitis and infertility). These men will generally have a normal follicle-stimulating hormone( FSH) and normal-sized testes.
Treatment options include IVF( intracytoplasmic sperm injection [ ICSI ]) and surgical sperm collection procedures
NEED TO KNOW
When assessing genetic factors in an infertile couple, it is essential to thoroughly review clinical indicators of risk for both female and male partners.
Consider requesting a pelvic ultrasound, semen analysis, AMH, karyotype and reproductive carrier screening when working up infertile couples for potential genetic causes.
A variety of assisted reproductive technologies may aid pregnancy in couples with genetic factors related to infertility, or genetic concerns, including a range of preimplantation genetic testing approaches, IVF-intracytoplasmic sperm injection and testicular sperm extraction.
Specialised genetic counselling is warranted for couples at risk or with concerns regarding genetic factors relevant to conception.
( testicular sperm aspiration [ TESA ], and testicular sperm extraction [ TESE or micro- TESE ]). With these procedures, pregnancy rates revert to being primarily dependent on the age of the female partner. It is important to exclude shared cystic fibrosis carrier status in the couple. It is important to note that different screening panels can have varying coverage of the CFTR gene variants, particularly in patients of non-European ethnicity. In particular, the Medicare-rebated threegene screen is a‘ hot spot’ panel of a limited number of common pathogenic variants, based on Caucasian population databases. Larger panels use next-generation sequencing of the entire CFTR coding sequence, for greater identification of rare or population-specific variants, and may be indicated in patients with non-European ancestry.
Non-obstructive azoospermia involves a failure in sperm production, and these men characteristically present with elevated FSH levels, small, soft testes, and often a small penis. Genetic causes include hypothalamic and pituitary deficiencies, Klinefelter syndrome( 47, XXY) and Y chromosome microdeletions. In past years these patients had limited reproductive options beyond donor sperm programs. Now, open testicular biopsies may reveal small nests of primitive sperm, even in patients with Klinefelter syndrome.
Genetic counselling is crucial when considering the underlying factors contributing to non-obstructive azoospermia. In some cases where sperm can still be surgically obtained, there may be a higher proportion of aneuploidy in the sperm.
Follow-up genetic testing of an embryo and / or pregnancy is dependent on a combination of the underlying genetic condition, the reproductive choices of the couple, and the technological limitations of