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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
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