From: The evolving role of genetic tests in reproductive medicine
Indications for genetic test | Genetic disorder | Frequency | Genetic test | Chromosome/genetic alterations | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. | |
---|---|---|---|---|---|---|---|---|---|---|
POI | Short stature, skeletal abnormalities, kidney problems, webbed neck, lymphedema; ovarian hypofunction or premature ovarian failure, infertility | Turner (45,X) (other names monosomy X, TS) | 1 in 2500 | Karyotype | Monosomy X: 45,X0 | ✓-donor | Not inherited | NA | POF | [87] |
Asymptomatic (only 10% of individuals with trisomy X are actually diagnosed); tall stature, epicanthal folds, hypotonia and clinodactyly; renal and genitourinary abnormalities; psychological problems | Trisomy X | 1/1000 | Karyotype | 47XXX or mosaic | ✓ | NA | ✓ | |||
Irregular menstrual cycles, early menopause, premature ovarian failure, infertility | Fragile X-associated primary ovarian insufficiency (premature ovarian failure 1) | 1 in 200 (4/6% of all cases of POI) | Molecular diagnosis of premutations in the FMR1 gene on chromosome Xq27.3 (CGG segment is repeated 55 to 200 times) | FMR1 gene | ✓-donor | X-linked | ✓ | POF | [88] | |
Hypogonadotropic hypogonadism; hypotonia, poor feeding, vomiting, weight loss, jaundice; impaired growth, cognitive deficit and cataracts | Galactosemia (galactose-1-phosphate uridyltransferase deficiency) | prevalence unknown; incidence 1/40,000–60,000 | Molecular diagnosis | GALT, GALK1, and GALE genes (9p13, 17q24, 1p36) | ✓ | AR | ✓ | POF | ||
Chronic mucocutaneous candidiasis, hypoparathyroidism and autoimmune adrenal failure; early onset | Autoimmune polyglandular syndrome (types 1) | Prevalence: 1–9 in 1,000,000; 1/25,000 in Finland | Molecular diagnosis | AIRE gene (21q22.3) | ✓ | AR | ✓ | IPEX syndrome; autoimmune polyendocrinopathy type 2 | ||
Hypertension, hypokalemia; abnormal sexual development, amenorrhea, infertility | 17α-hydroxylase deficiency | 1 in 1 million | Molecular diagnosis | CYP17A1 gene | Donor | AR | NA | Severe congenital adrenal hyperplasias | [45] | |
Mineralization of bones and osteoporosis; hyperglycemia; ambiguous genitalia, ovarian cysts early in childhood, anovulation; hirsutism | Aromatase deficiency | unknown | Molecular diagnosis | CYP19A1 gene | Donor | AR | NA | PCOS | ||
Ophthalmic disorder associated with premature ovarian failure; early onset | Blepharophimosis, ptosis, epicanthus inversus syndrome type I (BPES, type I) | Prevalence: 1–9/100 000 | Molecular diagnosis | FOXL2 gene | ✓ | AD or de novo | ✓ | PCOS | [89] | |
Pre- and postnatal growth retardation, facial sun-sensitive telangiectatic erythema, increased susceptibility to infections, and predisposition to cancer | Bloom syndrome | Unknown; 1/48,000 among people of Ashkenazi Jewish descent | Cytogenetic or molecular diagnosis | 15q26.1; BLM gene | ✓ | AR | ✓ | Silver–Russell syndrome, Rothmund–Thomson syndrome, ataxia–telangiectasia, Cockayne syndrome, and Nijmegen breakage syndrome | ||
Ovulation disorders (not POI) | Hypergonadotropic amenorrhea; lack of puberty; absence of secondary sexual features, decreased muscle mass, diminished libido, infertility | Kallmann | prevalence: 1/30,000; incidence: 1/8,000 | Molecular diagnosis | Type 1: ANOS1 Type 2 and 6: CHD7, FGFR1, FGF8 and SOX10 Type 3: FEZF1, PROK2, PROKR2 | ✓ | X-linked AD AR | ✓ | Syndromes associated with hypogonadotropic hypogonadism | |
Diabetes mellitus, hypothyroidism, alopecia totalis, long, triangular face, hypertelorism; dystonias, dysarthria, dysphagia | Woodhouse–Sakati syndrome | Unknown | Molecular diagnosis | DCAF17 gene | Donor | AR | NA | Diabetes; hypogonadism; deafness-intellectual disability | [27] | |
Hearing loss; intellectual disability, ataxia, peripheral neuropathy; ovarian dysgenesis, primary amenorrhea, primary ovarian insufficiency, normal external genitalia, infertility | Perrault syndrome | Rare | Molecular diagnosis | TWNK; CLPP; HARS; LARS2; HSD17B4 | Donor | AR | NA | Gonadal dysgenesis; sensorineural deafness | [90] | |
Gonadal dysgenesis, XX type, with deafness | ||||||||||
Ovarian dysgenesis with sensorineural deafness | ||||||||||
Primary amenorrhea, infertility, polycystic ovarian syndrome, hirsutism, ambiguous genitalia | Cytochrome P450 oxidoreductase deficiency | Unknown | Molecular diagnosis | POR gene | Donor | AR | NA | PCOS | [91] | |
Skeletal abnormalities, craniosynostosis, a flattened mid-face, a prominent forehead, and low-set ears; arachnodactyly, choanal atresia; primary amenorrhea, infertility, polycystic ovarian syndrome, hirsutism, ambiguous genitalia | Antley–Bixler syndrome | Unknown | Molecular diagnosis | FGFR2 gene | Donor | AR | NA | PCOS | [92] | |
Obesity, hirsutism, and amenorrhea are clinical correlates of enlarged polycystic ovaries | Polycystic ovary syndrome (PCOS) | 6 to 10% of women worldwide | Molecular diagnosis | AOPEP; AR; DENND1A; ERBB4; FSHB; FSHR; FTO; GATA4; HMGA2; INSR; KRR1; LHCGR; RAB5B; RAD50; SUMO1P1; SUOX; THADA; TOX3; YAP1 | ✓ | Does not have a clear pattern of inheritance | NA | Amenorrhea | ||
Polycystic ovary syndrome 1 (STEIN-LEVENTHAL SYNDROME HYPERANDROGENEMIA) | Molecular diagnosis | PCOS1 | ✓ | AD | NA | Amenorrhea; HYPERANDROGENEMIA | ||||
Hydropic placental villi, trophoblastic hyperplasia, and poor fetal development | Recurrent hydatidiform mole-type 1 (familial recurrent hydatidiform mole, FRHM) | 1:250 in eastern Asia | Molecular diagnosis | NLRP7 gene (55%); KHDC3L gene (5%) | ✓ | AR | ✓ | Hydatidiform mole | ||
Abnormally developed embryo and placenta that result in the formation of hydatidiform moles | Hydatidiform mole | 1:1500 in USA | Molecular diagnosis | C11 or F80, MEI1, REC114 | ✓ | AR | ✓ | FRHM | ||
Normal general physical examination, absence of clinical findings involving other organ systems; typical female external genitalia, normally formed uterus and fallopian tubes, gonadal dysgenesis; skeletal abnormalities, campomelic dysplasia | Swyer syndrome (46,XY complete gonadal dysgenesis) | 1 in 80,000 | Molecular diagnosis | SRY (15%); MAP3K1 (18%); DHH and NR5A1 (rare) | ART | De novo; rare AD | ✓ | Ambiguous genitalia and/or sex chromosome-phenotype discordance | [69] |