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Table 3 The genetic causes related to pretesticular male infertility: from the first observation to the report

From: The evolving role of genetic tests in reproductive medicine

Main indications for genetic test Hypogonadotropic hypogonadism (CHH)
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 [21, 22]
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)  [21, 23,24,25]
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 [28,29,30]
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 [31,32,33,34]
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 [35, 36]
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 [38, 39]
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 [40,41,42]
  1. Database sources: NIH, OMIM and OrphaNet
  2. , yes; ✗, no; NA, not applicable; donor, heterologous fertilization with sperm donor