What are the genetic causes of premature ovarian insufficiency?

[Tier B — the ASRM/ESHRE premature ovarian insufficiency guidance was not available to this audit] Established genetic causes fall into recognisable groups: Chromosomal. Turner syndrome (45,X and mosaic variants) is the commonest. Other X-chromosome abnormalities including deletions, translocations and isochromosomes also cause POI, reflecting the requirement for two intact X chromosomes for normal ovarian development. FMR1 premutation. Carriers of the fragile X premutation (approximately 55–200 CGG repeats) have a substantially increased risk of POI. This is the most important single gene test in practice, because a positive result has implications extending well beyond the woman herself — for her future children, and for relatives who may be at risk of fragile X syndrome or FXTAS. Cascade testing and genetic counselling are required. Single gene causes. A growing list including genes involved in follicle development, meiosis and DNA repair. Individually rare; collectively a meaningful proportion of cases. Syndromic associations. Galactosaemia, BPES, autoimmune polyglandular syndromes. Minimum testing in POI: karyotype and FMR1 premutation analysis. Autoimmune screening including adrenal antibodies is also standard, as autoimmune POI carries a risk of adrenal insufficiency. Verified against the joint ESHRE/ASRM/CRE-WHiRL/IMS POI guideline (Fertil Steril 2025;123(2):221-36): Diagnosis requires only ONE elevated FSH >25 IU — changed from two measurements in the 2015 version, specifically to enable prompt diagnosis and treatment. AMH may confirm where FSH is inconclusive but is not a primary diagnostic test, and is not recommended for predicting POI. Chromosomal analysis and FMR1 premutation testing are both STRONG recommendations for all women with non-iatrogenic POI. Note FMR1 requires a specific test — multigene panels and NGS do not detect the premutation. Additional NGS may be offered (conditional). Age should not restrict access to testing. 21-hydroxylase autoantibody screening is recommended in POI of unknown cause (strong); positive results warrant endocrinology referral for adrenal function testing. Anti-ovarian antibodies should NOT be used (strong). TSH at diagnosis, repeated every 5 years (strong). TPO antibody screening is NOT routinely recommended. Prevalence is now reported at 3.5%, higher than older estimates of ~1%. POI without hormone therapy is associated with reduced life expectancy, largely cardiovascular (strong). HT is recommended until the usual age of menopause for primary prevention, whether or not oestrogen deficiency symptoms are present (strong). Female relatives are at increased risk and should be counselled (strong); there are no established methods for predicting or preventing POI.