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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

✓

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

[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