Presentation: Patient with possible premature ovarian insufficiency

A 25-year-old female is referred to the endocrine clinic by her GP because of increasingly infrequent periods and high follicle-stimulating hormone (FSH) levels.

Indications for genomic testing in patients with possible premature ovarian insufficiency (POI) are a confirmed diagnosis of POI, which requires both:

• four consecutive months of disordered menstrual cycles (spontaneous amenorrhea – primary or secondary – or irregular menstrual cycles); and
• elevated serum FSH of over 25IU/L (repeated 4–6 weeks later if there is diagnostic uncertainty) that is non-iatrogenic in origin.

This genomic testing is available on the National Genomic Test Directory panel and includes Fragile X screening and a karyotype. Beyond this, where available (for example, in a research context) and after comprehensive genetic counselling, additional genomic testing (for example, massively parallel sequencing (NGS)) can be offered to all women with non-iatrogenic POI to identify other potential genes that may cause POI.

Turner syndrome may be suspected at different ages due to various phenotypic features, including:

• short stature;
• micrognathia;
• widened carrying angle;
• low hairline;
• webbed neck;
• widely spaced nipples;
• high arched palate;
• nail dysplasia;
• scoliosis;
• high blood pressure;
• autoimmune hypothyroidism; and
• horseshoe kidney.

Fragile X syndrome may be suspected if there is a learning difficulty, family history of the disease or unexplained ataxia with onset in adulthood.

Autoimmune polyendocrinopathy syndrome types 1 and 2 are usually associated with other autoimmune problems (such as mucocutaneous candidiasis, hypoparathyroidism, Addison disease, hypothyroidism, type 1 diabetes and pernicious anaemia).

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• If a patient meets the test directory criteria for POI, select:
  • R402 Premature ovarian insufficiency: this includes karyotype testing and short tandem repeat (STR) testing for the gene associated with Fragile X syndrome.
• If you suspect Turner syndrome, select:
  • R26 Likely common aneuploidy: this should be selected if you want to focus your investigations on the common aneuploidies (it tests for trisomy 13, trisomy 18, trisomy 21 and Turner syndrome);
  • R265 Chromosomal mosaicism – karyotype: this may be considered if the clinical picture is strongly suggestive of Turner Syndrome but R26 is negative (it involves karyotyping an extended number of cells in order to identify mosaicism); and
  • R137 Congenital heart disease – microarray: this should be selected if you are investigating a chromosomal cause for congenital heart disease (it will identify Turner syndrome as well as other chromosomal causes). You may wish to consult Presentation: Infant or child with congenital heart disease.
• If you suspect autoimmune polyendocrine syndrome type 1, select:
  • R155 Autoimmune polyendocrine syndrome: this involves AIRE single gene testing.
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion, or RoD) form. If your laboratory doesn’t have a non-WGS RoD form, you can use this template non-WGS RoD (PDF).
• R265 may only be requested following discussion with a clinical genetics team or your local genomics laboratory.
• If the tests outlined above return negative results, whole exome sequencing could identify rare variants in genes associated with POI (for example FSHR, GDF9, BMP15, FIGLA, NOBOX, LHCGR, SPIDR, BMPR2, MSH4, MSH5, GJA4, FANCM, POLR2C, MRPS22, KHDRBS1, BNC1, WDR62, ATG7/ATG9, BRCA2, NOTCH2, POLR3H, TP63, NR5A1, STAR, BMP15, YTHDC2, ZSWIM7, and GDF9); however, this genetic testing approach is currently not supported within the NHS for a POI diagnosis and variants in many of genes are of uncertain significance.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory
• NHS Health A to Z: Turner syndrome

For patients

• Daisy Network (a charity for women with POI)
• Fragile X Society
• National Organization for Rare Disorders: Turner syndrome
• NHS Health A to Z: Turner syndrome
• Turner Syndrome Support Society