Introduction
Materials and methods
Results
Genetic tests in the identification of the causes of infertility
Indications for genetic test | Genetic condition | Frequency | Test | Chromosome/genetic alterations | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. |
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Azoospermia/oligozoospermia; Sertoli cell syndrome type I and type II (presence of some tubules with normal spermatogenesis) and hypospermatogenesis diagnosis by histological evaluation | Microdeletion Y chromosome AZFc | 1/2.500; (AZFc 60%, AZFb 15%, AZFb-c 22%, AZFa 3%); 13% of azoospermia cases; 3–7% of oligozoospermia cases | Molecular diagnosis by PCR of STS sequences | Interstitial deletion of AZFc Y region (recombination between palindromes b2 and b4); DAZ, BPY2, PRY2, CDY1 | ✓: testicular sperm retrieval + ICSI | Y linked | ✓ | Other causes of azoospermia or oligozoospermia | [10] |
Azoospermia; spermatogenesis arrest by histological evaluation | Microdeletion Y chromosome AZFb | Interstitial deletion of AZFb Y region (deletions P5/proximal-P1); RBMY, CDY, HSFY, PRY | |||||||
Azoospermia | Microdeletion Y chromosome AZFb-c | Combined deletion AZFb + AZFc (P5/distal-P1 or P4/distal-P1) | ✓: donor | NA | NA | ||||
Azoospermia; Sertoli cell syndrome type I diagnosis by histological evaluation (i.e., complete absence of germ cells in seminiferous tubules) | Microdeletion Y chromosome AZFa | Deletion of AZFa Y (recombination between HERV15yq1 and HERV15yq2) |
Indications for genetic test | Genetic condition | Frequency | Test | Chromosome/genetic alterations | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. |
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Hypergonadotropic hypogonadism, ↑FSH ↑LH ↓T, azoospermia, oligozoospermia; small testes, infertility, gynecomastia; neurocognitive deficits; metabolic syndrome, type 2 diabetes. Approximately 10% of these subjects have spermatozoa in the ejaculate, and in 30–50% of cases there is intratesticular spermatogenesis | Klinefelter’s syndrome | 1/660 newborns; > 5% in severe oligozoospermia; 10% in azoospermia | Karyotype | 47,XXY (85–90%) 46,XY/47,XXY mosaicism (6–7%) 46,XX/47,XXY or multiple X aneuploidy (3–8%) | ✓ Testicular sperm retrieval + ICSI | De novo mutation | NA | 46,XX testicular DSD | |
Short stature; gynecomastia, male external genitalia, small testes, cryptorchidism, hypospadias, infertility, ↑FSH ↑LH↓T; azoospermia/oligozoospermia | Nonsyndromic 46,XX Testicular Disorders of Sex Development (De la Chapelle syndrome) | 1/20.000; 0,9% in azoospermia; 1–3% normospermia | FISH or CMA | SRY+ XX (80–90%) | ✗ Testicular sperm retrieval; ✓ heterologous fertilization | AD | ✓ | Syndromic forms of 46,XX testicular DSD; 45X/46,XY; 47,XXY; 46,XX; sex chromosome mosaicisms; Prenatal exposure of 46,XX fetuses to androgens | [13] |
Penoscrotal hypospadias, cryptorchidism, infertility; ↑FSH ↑LH↓T; azoospermia/oligozoospermia | SRY− XX (< 10%) | Unknown | ✓ | ||||||
Short stature; small testes, infertility; ↑FSH ↑LH↓T; azoospermia/oligozoospermia | CMA or molecular diagnostic by PCR | CNV or rearrangements in SOX9, SOX3, RSPO1 and WNT4 (rare) | ✓AD for SOX9; AR for RSPO1 or WNT4 | ✓ | 46,XX; 46,XY disorders of sex development | ||||
Tall stature, delayed development of speech, language or motor skills, autism spectrum disorder, hypotonia, motor tics, clinodactyly, scoliosis, attention deficit hyperactivity disorder; ↑FSH normal or ↓T; from normal to azoospermia; from 0.57 to 77.8% sperm mosaicism, a- or hyper diploidy | Double Y syndrome (Jacobs syndrome) | 1/1.000; 0.4% in oligozoospermia | Cytogenetics tests | 47,XYY; 46,XY/47,XYY mosaics | ✓IVF or ICSI in case of oligospermic patients | Does not have a clear pattern of inheritance | ✓ | 46,XY | |
Subfertility or uneventful andrological history; oligozoospermia | Balanced structural chromosome aberrations | 5% of infertile men | FISH | t(SRY; X); der(13, 14); der(14, 21); der(14, 15) | ✓ | NA | ✓ PGT | Other causes of oligozoospermia | [20] |
Male genetic infertility
Main indications for genetic test | Hypogonadotropic hypogonadism (CHH) | ||||||||
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Other indications for genetic test | Genetic disorder | Frequency | Genetic test | Genetic alterations | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. |
Lack of puberty; micropenis, cryptorchidism; prepubertal testicular volume, absence of secondary sexual features, decreased muscle mass, diminished libido, erectile dysfunction, infertility, low testosterone, estradiol | Kallmann syndrome (olfactogenital syndrome with ano- or hyposmia azoospermia) | Prevalence: 1/30,000; incidence: 1/8000 | Molecular diagnosis | ANOS1 | ✓ | X-linked | ✓ | Syndromes associated with hypogonadotropic hypogonadism | |
CHD7, FGFR1, FGF8, SOX10 | AD | ||||||||
FEZF1, PROK2, PROKR2 | AR | ||||||||
Obesity, retinitis pigmentosa, postaxial polydactyly, kidney dysfunction, behavioral dysfunction; infertility | Bardet–Biedl syndrome (Laurence–Moon–Biedl syndrome) | 1:100,000 North America; 1:160,000 Switzerland; 1:17,500 Newfoundland; 1:13,500 Bedouin, Kuwait | Multigene panel | From BBS1 to BBS19 | ✓ | AR | ✓ | McKusick–Kaufman syndrome (MKS) | |
Adrenal insufficiency; cryptorchidism, delayed puberty, infertility | X-linked adrenal hypoplasia congenita | 1:12,500 | Molecular diagnosis | NR0B1 | ✓ | X-linked recessive pattern | ✓ | 21-hydroxylase deficiency; 11-hydroxylase deficiency | [26] |
Diabetes mellitus, hypothyroidism, alopecia totalis, long, triangular face, hypertelorism; dystonias, dysarthria, dysphagia; infertility | Woodhouse–Sakati syndrome (diabetes-hypogonadism-deafness-intellectual disability syndrome) | Unknown | Molecular diagnosis | DCAF17 | ✓ | AR | ✓ | Perrault syndrome; Deafness and hereditary hearing loss; Gonadotropin-releasing hormone deficiency | [27] |
Adult-onset neurodegenerative disorder; hypogonadotropic hypogonadism | Gordon Holmes syndrome (cerebellar ataxia and hypogonadotropic hypogonadism) | Unknown | Molecular diagnosis | RNF216, PNPLA6 | ✓ | AR | ✓ | Cerebellar ataxia | |
Cirrhosis, diabetes, cardiomyopathy, arthritis, skin hyperpigmentation; elevated serum transferrin-iron saturation (TS); elevated serum ferritin concentration; infertility | Hemochromatosis (Hemochromatosis Type 1, HFE-Associated Hemochromatosis, HFE-HH) | 2–5:1000 northern European ancestry; 1:200–400 non-Hispanic whites, North America | Gene-targeted or molecular diagnosis | HFE (typically p.Cys282Tyr and p.His63Asp can be performed first) | ✓ | AR | NA | Rarer primary iron overload disorders and secondary iron overload disorders | |
Azoospermia/oligozoospermia; ↑LH, normal T, hyperandrogenism; feminization of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility | Androgen insensitivity syndrome (AIS) | 2–5:100,000 | Screening for AR mutations (> 300) | AR | Donor | X-linked recessive | NA | MRKH syndrome; Hypospadias; MAIS; Undermasculinization of external genitalia and pubertal undervirilization | |
Glucocorticoid and mineralocorticoid deficiencies; hypospadias; ambiguous genitalia, infertility | 3-β-hydroxysteroid dehydrogenase (HSD) deficiency | Unknown | Molecular diagnosis | HSD3B2 | Donor | AR | NA | Ambiguous genitalia | [37] |
Deficiencies in GH,TSH, LH, FSH, PrL, and ACTH; hypothyroidism; neonatal hypoglycemia; micropenis without hypospadias, with or without cryptorchidism; short stature and delayed bone maturation; absent/delayed/incomplete secondary sexual development, infertility | PROP1-related combined pituitary hormone deficiency | 1:4000 in England and the US | Molecular diagnosis | PROP1 | ✓ | AR | ✓ | CPHD; isolated growth hormone deficiency; isolated hypogonadotropic hypogonadism | |
Ambiguous genitalia or external genitalia that appear female; micropenis and hypospadias; not much facial or body hair; infertility | 5-Alpha reductase deficiency (familial incomplete male pseudohermaphroditism, type 2) | Unknown | Molecular diagnosis | SRD5A2 | ✓ | AR | ✓ | Ambiguous genitalia |
Indications for genetic test | Genetic disorder | Frequency | Genetic test | Chromosome/genetic alterations | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. |
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Maldescended testes | |||||||||
Absence of one or both testes from the scrotum; nonobstructive azoospermia; hypogonadotropic hypogonadism | Cryptorchidism | 2%; 20% of infertile men; 30/80% of azoospermia | Molecular diagnosis | INSL3; LGR8 | ✓ | AD | ✓ | Hypogonadotropic hypogonadism; Noonan and Prader–Willi syndrome | |
Hypertension, hypokalemic alkalosis; lack of secondary sexual characteristics; testicular feminization | 17 alpha(α)-hydroxylase/17,20-lyase deficiency | 1 in 1 million | Molecular diagnosis | CYP17A1 | Donor | AR | NA | Ambiguous genitalia | [45] |
Severe muscular hypotonia, genital hypoplasia, incomplete pubertal development, infertility; cryptorchidism (93%); obesity, mental retardation (late onset) | Prader–Willi syndrome (PWS, Prader–Labhart–Willi syndrome) | 1:10,000 to 1:30,000 | DNA methylation testing; Cytogenetic/FISH/chromosomal microarray findings: deletion in bands 15q11.2-q13 (70%) | 15q11.2 region | Donor | Paternal deletion; maternal uniparental disomy15 | ✓ | Cryptorchidism; Craniopharyngioma | |
Short stature, facial dysmorphism, congenital heart defects, skeletal defects, webbed neck, mental retardation, bleeding diathesis; early onset | Noonan syndrome-1 (NS1) | 1:1000–2500 | Gene sequencing starting with PTPN11, followed by SOS1, KRAS and RAF1 | PTPN11 (> 50%), SOS1 (10–15%), KRAS (5%), RAF1 (3–17%) | ✓ | AD | ✓ | Turner syndrome; cryptorchidism; azoospermia | [49] |
Gonadal dysgenesis, ambiguous genitalia, infertility; increased risk of Wilms tumor | Denys–Drash syndrome | Unknown | Molecular diagnosis | WT1 | – | AD | ✓ | Frasier syndrome | |
Atrophy of the abdominal muscles, malformations of the urinary tract | Prune–belly syndrome (other names Syndrom of Eagle–Barret; syndrom of Obrinsky) | 1/35,000 and 1/50,000 births and 95% of cases occur in males | Molecular diagnosis | CHRM3 | NA | – | NA | Megacystis/megaureter or posterior urethral valves | |
Osteoporosis; hyperglycemia; ambiguous genitalia | Aromatase deficiency | Unknown | Molecular diagnosis | CYP19A1 | ✓ | AR | ✓ | Other condition of estrogen deficiency | |
Proportionate short stature, delayed closure of fontanelles, prominent forehead, drooping shoulders, abnormal dental development; early onset | Cleidocranial dysplasia | 1:1,000,000 | Molecular diagnosis | RUNX2 (CBFA1) | ✓ | AD; de novo pathogenic variant | ✓ | Pycnodysostosis; mandibuloacral dysplasia; CBFB | |
Syndromic without maldescended testes | |||||||||
Short stature, telangiectatic erythematous skin lesions, high risk for malignancies; early onset; azoospermia or severe oligospermia | Bloom’ s syndrome (Bloom–Torre–Machacek syndrome) | Rare disorder | Molecular diagnosis | BLM | ✓ | AR | ✓ | RECQ-mediated genome instability; Ataxia–telangiectasia; Fanconi; anemia; Nijmegen breakage syndrome; Werner syndrome | |
Short stature, macrocephaly, distinctive face (small, triangular face with prominent forehead, narrow chin, small jaw), delayed development, speech and language problems, learning disabilities; digestive system abnormalities; micropenis; early onset | Russel–Silver syndrome | Prevalence: unknown; estimated incidence ranges from 1 in 30,000–1 in 100,000 people | Methylation | Methylation involving H19 and IGF2 | ✓ | Sporadic; uniparental disomy | Usually not possible | Intrauterine growth retardation and short stature | |
Keratoconus, glaucoma, and myopia as well as from malformations of the brain, skeleton, and kidney; impairment of respiratory functions; infertility (asthenozoospermia and abnormal flagellar morphology) | Primary ciliary dyskinesia (PCD) | Prevalence: 1:16,000; 1:400 in a Volendam population residing in a fishing village of North Holland | Molecular diagnosis | DNAH5 (30%), DNAI1 (10%) and TXNDC3, DNAH11, DNAI2 (rare); 60% gene loci unknown | ICSI | AR | ✓ | Chronic sinopulmonary disease and bronchiectasis | |
Multisystem disorder affecting the skeletal and smooth muscles, the heart, the eyes, and the endocrine and central nervous systems. Mental retardation; infertility | Myotonic dystrophy 1 (Morbus Curschmann–Steinert, Dystrophia myotonica 1, DM1) | 1 in 8000 | Molecular diagnosis of the CTG repeat expansion in the DMPK gene (> 50 CTG repeats result in DM1) | DMPK | ✓ | AD | ✓ | Prader–Willi syndrome, nemaline myopathy, X-linked centronuclear myopathy; DM2; Hereditary distal myopathies; Hereditary myotonia | |
Bone marrow failure, hypopigmentation, short stature, physical abnormalities, organ defects (gastrointestinal abnormalities; heart defects; and eye abnormalities, malformed ears and hearing loss); increased risk of certain cancers; and malformations of the reproductive system and infertility | Fanconi anemia | 1 in 160,000 (more common among people of Ashkenazi Jewish descent, the Roma population of Spain, and black South Africans) | Molecular diagnosis | FANCA, FANCC and FANCG (90%) | NA | AR; AD:RAD51-related FA; X-linked: FANCB-related FA | ✓ | Bloom syndrome; ataxia–telangiectasia; NBS; Seckel syndrome; neurofibromatosis 1 | |
Nonsyndromic infertility | |||||||||
Abnormal sperm cells (round head and no acrosome) and infertility | Globozoospermia (spermatogenic failure 9) | Rare (1:65,000); common in North Africa: 1:100 cases of male infertility | Molecular diagnosis of DPY19L2, followed by SPATA16 | DPY19L2 homozygous deletion, point mutations; SPATA16 | ✓ ICSI + AOA | AR | ✓ | Spermatogenic failure | |
Abnormal sperm cells (abnormally large and misshapen heads, contains extra chromosomes; multiple flagella, most often four) and infertility | Macrozoospermia (spermatogenic failure 5) | Unknown;1:10,000 males in North Africa | Molecular diagnosis | AURKC mutations (c.144delC, 85%; p.Y248, DR 13%) | Donor | AR | NA | Spermatogenic failure | |
Primary infertility; multiple morphological abnormalities of sperm flagella (absent, short, coiled, bent, and irregular flagella); asthenozoospermia | Multiple morphological abnormalities of the sperm flagella (spermatogenic failure 18) | Unknown | Molecular diagnosis | DNAH1 mutation (c.8626-1G > A; c.3860 T > G) | ✓ ICSI | AR | NA | Ciliary dyskinesia primary | [69] |
Genital abnormalities; hypoplasia of Leydig cells; micropenis, hypospadias, bifid scrotum, ambiguous genitalia | Leydig cell hypoplasia (hypergonadotropic hypogonadism due to LHCGR defect) | Unknown | Molecular diagnosis | LHCGR | Donor | AR | ✓ | Hypergonadotropic hypogonadism | |
Asthenozoospermia; absence of any other symptoms | CATSPER-related nonsyndromic male infertility | Unknown | Molecular diagnosis | CATSPER1, GALNTL5 | Donor | AR | ✓ | Male infertility | |
Normal general physical examination, absence of clinical findings involving other organ systems; typical female external genitalia, uterus and fallopian tubes normally formed, 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 | [13] |
Asthenozoospermia; hearing loss | Deafness-infertility syndrome (DIS) | Unknown | CMA/array-CGH | Homozygous deletion at 15q15.3 including CATSPER2, STRC | Donor | AR | ✓ | DFNB16 | |
Nonobstructive azoospermia | |||||||||
Small testes and infertility, with severe oligozoospermia or nonobstructive azoospermia due to maturation arrest at the primary spermatocyte stage | Meiotic arrest at primary spermatocyte stage (spermatogenic failure 25) | Unknown | Molecular diagnosis | TEX11 | Donor | X-linked | NA | Spermatogenic failure | |
Nonobstructive azoospermia, infertility, testicular biopsy showing absence of spermatogenic cells and a Sertoli cell-only pattern | Spermatogenic failure 32 | Unknown | Molecular diagnosis | SOHLH1 | Donor | AD | NA | Spermatogenic failure | [79] |
Azoospermia; testicular histology showing arrest of spermatogenesis at the pachytene stage of primary spermatocytes | Spermatogenic failure 4 (SPGF4) | 1% | Molecular diagnosis | SYCP3 (COR1 RPRGL4 SCP3 SPGF4) | Donor | AD | NA | Spermatogenic failure | [80] |
Azoospermia or oligozoospermia | Spermatogenic failure, Y-linked 2 | Unknown | Molecular diagnosis | RBMY1A1, DAZ1–4 | Donor | Y-linked | NA | Spermatogenic failure |
Main indications for genetic test | Obstructive azoospermia or severe oligospermia | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. | |||
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Genetic disorder | Frequency | Genetic test | Genetic alteration | ||||||
Abnormalities of seminal vesicles or absence of vas deferens; normal testicular development and function; normal spermatogenesis; a low volume of ejaculated semen with a specific profile (volume < 1.5 ml, ph < 7.0, elevated citric acid concentration, elevated acid phosphatase concentration, low fructose concentration, and failure to coagulate) | Congenital bilateral absence of the vas deferens (CBAVD) | 25%; 1–2% in infertility | Screening for CFTR mutations | Two CFTR pathogenic variants identified (46%); one CFTR pathogenic variant identified (79%) | ✓ ICSI | AR | ✓ | Young syndrome; Hereditary urogenital dysplasia | |
Multisystem disease affecting epithelia of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and exocrine sweat glands; obstructive azoospermia and male infertility | Cystic fibrosis | 1:3200; CF occurs with lower frequency in other ethnic and racial populations (1:15,000 African Americans, and 1:31,000 Asian Americans) | Screening for CFTR mutations | Two CFTR pathogenic variants identified | ✓ ICSI | AR | ✓ | Asthma; congenital airway anomalies; primary ciliary dyskinesia; Shwachman–Diamond syndrome; Bronchiectasis with or without elevated sweat chloride; Isolated hyperchlorhidrosis; Congenital bilateral absence of the vas deferens (CBAVD) |
Female genetic infertility
Indications for genetic test | Genetic disorder | Frequency | Genetic test | Chromosome/genetic alterations | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. | |
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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] |
Indications for genetic test | Genetic disorder | Frequency | Genetic test | Genetic alterations | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. |
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Underdeveloped or absent uterus and abnormalities of other reproductive organs; normal female external genitalia, breasts; hyperandrogenism; facial hirsutism; primary amenorrhea; infertility | Müllerian aplasia and hyperandrogenism (other names: Biason–Lauber syndrome, WNT4 deficiency) | Rare | Molecular diagnosis | WNT4 gene | NA | AD or de novo | ✓ | Abnormalities of the reproductive system | |
Vagina and uterus to be underdeveloped or absent, although external genitalia are normal, primary amenorrhea | Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome (type 1) | 1 in 4500 | Molecular diagnosis | ESR1, OXTR, WNT9B | NA | AD | ✓ | Abnormalities of the reproductive system | |
Underdeveloped or absent vagina and uterus, although external genitalia are normal; primary amenorrhea; unilateral renal agenesis; skeletal abnormalities; hearing loss or heart defects | Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome (type 2) | ||||||||
Bone marrow failure, hypopigmentation, short stature, physical abnormalities, organ defects (gastrointestinal abnormalities; heart defects; eye abnormalities, malformed ears and hearing loss), and an increased risk of certain cancers; abnormal genitalia or malformations of the reproductive system and infertility | Fanconi anemia (Fanconi pancytopenia Fanconi panmyelopathy) | 1 in 160,000 (more common among people of Ashkenazi Jewish descent, the Roma population of Spain, and black South Africans) | Molecular diagnosis | FANCA, FANCC and FANCG (90%) | NA | AR; AD (RAD51-related FA); X-linked (FANCB-related FA). | ✓ | Bloom syndrome; ataxia–telangiectasia, Nijmegen breakage syndrome (NBS); Seckel syndrome; neurofibromatosis 1; POI |