Table 4.
The genetic causes related to testicular male infertility: from the first observation to the report
| 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, 46–48] |
| 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 | [66–68] |
| 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 | [76–78] |
| 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] |
Database sources: NIH, OMIM and OrphaNet
✓, yes; ✗, no; NA, not applicable; donor, heterologous fertilization with sperm donor; AOA, assisted ovarian activation, CMA, chromosomal microarray analysis