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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