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Table 6 The genetic causes related to ovarian female infertility: from the first observation to the report

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  [62, 63]
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
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 [93, 94]
Polycystic ovary syndrome 1 (STEIN-LEVENTHAL SYNDROME HYPERANDROGENEMIA) Molecular diagnosis PCOS1 AD NA Amenorrhea; HYPERANDROGENEMIA [93, 94]
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 [95, 96]
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 [95, 96]
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]
  1. Database sources: NIH, OMIM and OrphaNet
  2. , yes; ✗, no; NA, not applicable; POF, premature ovarian failure; PCOS, polycystic ovarian syndrome