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Table 4 The genetic causes related to testicular male 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.

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

[43, 44]

 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

[21, 46,47,48]

 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

[50, 51]

 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

[52, 53]

 Osteoporosis; hyperglycemia; ambiguous genitalia

Aromatase deficiency

Unknown

Molecular diagnosis

 CYP19A1 

✓

AR

✓

Other condition of estrogen deficiency

[54, 55]

 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

[21, 56]

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

[21, 57]

 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

[21, 58, 59]

 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

[21, 60]

 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

[21, 61]

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

[62, 63]

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

[64, 65]

 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

[66,67,68]

 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

[70, 71]

 Asthenozoospermia; absence of any other symptoms

CATSPER-related nonsyndromic male infertility

Unknown

Molecular diagnosis

CATSPER1, GALNTL5

Donor

AR

✓

Male infertility

[69, 72, 73]

 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

[74, 75]

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

[76,77,78]

 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

[81, 82]

  1. Database sources: NIH, OMIM and OrphaNet
  2. ✓, yes; ✗, no; NA, not applicable; donor, heterologous fertilization with sperm donor; AOA, assisted ovarian activation, CMA, chromosomal microarray analysis