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Table 2 The chromosome aberrations related to pretesticular male infertility: from the first observation to the report

From: The evolving role of genetic tests in reproductive medicine

Indications for genetic test Genetic condition Frequency Test Chromosome/genetic alterations ART Inheritance Antenatal test Differential diagnosis Refs.
Hypergonadotropic hypogonadism, ↑FSH ↑LH ↓T, azoospermia, oligozoospermia; small testes, infertility, gynecomastia; neurocognitive deficits; metabolic syndrome, type 2 diabetes. Approximately 10% of these subjects have spermatozoa in the ejaculate, and in 30–50% of cases there is intratesticular spermatogenesis Klinefelter’s syndrome 1/660 newborns; > 5% in severe oligozoospermia; 10% in azoospermia Karyotype 47,XXY (85–90%)
46,XY/47,XXY mosaicism (6–7%)
46,XX/47,XXY or multiple X aneuploidy (3–8%)
Testicular sperm retrieval + ICSI De novo mutation NA 46,XX testicular DSD [11, 12]
Short stature; gynecomastia, male external genitalia, small testes, cryptorchidism, hypospadias, infertility, ↑FSH ↑LH↓T; azoospermia/oligozoospermia Nonsyndromic 46,XX Testicular Disorders of Sex Development (De la Chapelle syndrome) 1/20.000; 0,9% in azoospermia; 1–3% normospermia FISH or CMA SRY+ XX (80–90%) ✗ Testicular sperm retrieval; heterologous fertilization AD Syndromic forms of 46,XX testicular DSD; 45X/46,XY; 47,XXY; 46,XX; sex chromosome mosaicisms; Prenatal exposure of 46,XX fetuses to androgens [13]
Penoscrotal hypospadias, cryptorchidism, infertility; ↑FSH ↑LH↓T; azoospermia/oligozoospermia SRY XX (< 10%) Unknown
Short stature; small testes, infertility; ↑FSH ↑LH↓T; azoospermia/oligozoospermia CMA or molecular diagnostic by PCR CNV or rearrangements in SOX9, SOX3, RSPO1 and WNT4 (rare) AD for SOX9; AR for RSPO1 or WNT4 46,XX; 46,XY disorders of sex development [14,15,16,17,18]
Tall stature, delayed development of speech, language or motor skills, autism spectrum disorder, hypotonia, motor tics, clinodactyly, scoliosis, attention deficit hyperactivity disorder; ↑FSH normal or ↓T; from normal to azoospermia; from 0.57 to 77.8% sperm mosaicism, a- or hyper diploidy Double Y syndrome (Jacobs syndrome) 1/1.000; 0.4% in oligozoospermia Cytogenetics tests 47,XYY; 46,XY/47,XYY mosaics IVF or ICSI in case of oligospermic patients Does not have a clear pattern of inheritance 46,XY [14, 19]
Subfertility or uneventful andrological history; oligozoospermia Balanced structural chromosome aberrations 5% of infertile men FISH t(SRY; X); der(13, 14); der(14, 21); der(14, 15) NA PGT Other causes of oligozoospermia [20]
  1. Database sources: NIH, OMIM and OrphaNet
  2. , yes; ✗, no; NA, not applicable; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; FISH, fluorescence in situ hybridization; PGT: preimplantation genetic testing; CMA, chromosomal microarray analysis