Abstract
The objective of the present study was to determine the frequency of somatic chromosomal anomalies and Y chromosomal microdeletions (azoospermia factor genes, AZF) in infertile males who seek assisted reproduction. These studies are very important because the assisted reproduction techniques (mainly intracytoplasmic sperm injection) bypass the natural selection process and some classical chromosomal abnormalities, microdeletions of AZF genes or some deleterious genic mutations could pass through generations. These genetic abnormalities can cause in the offspring of these patients male infertility, ambiguous external genitalia, mental retardation, and other birth defects. We studied 165 infertile men whose infertility was attributable to testicular problems (60 were azoospermic, 100 were oligospermic and 5 were asthenospermic). We studied 100 metaphases per patient with GTG banding obtained from temporary lymphocyte culture for chromosomal abnormality detection and performed a genomic DNA analysis using 28 Y chromosome-specific sequence-tagged sites for Y AZF microdeletion detection. Karyotyping revealed somatic anomalies in 16 subjects (16/165 = 9.6%). Of these 16, 12 were in the azoospermic group (12/60 = 20%) and 4 were in the oligospermic group (4/100 = 4%). The most common chromosomal anomaly was Klinefelter syndrome (10/165 = 6%). Microdeletions of AZF genes were detected in 12 subjects (12/160 = 7.5%). The frequencies detected are similar to those described previously. These results show the importance of genetic evaluation of infertile males prior to assisted reproduction. Such evaluation can lead to genetic counseling and, consequently, to primary and secondary prevention of mental retardation and birth defects.
Highlights
The genetic factors most frequently related to male infertility are somatic chromosomal anomalies and Y chromosomal microdeletions within the Yq11 region, where the genes that control spermatogenesis, known as azoospermia factor genes (AZF), are located [1].The incidence of somatic chromosomal anomalies in the infertile male population is approximately 10% and this frequency increases as the sperm concentration in ejaculate decreases [2]
Microdeletions of the AZF genes are caused by intrachromosomal recombination events between large homologous repetitive sequence blocks, and it is currently accepted that AZFb contains eight protein-coding genes (CDY2, EIF1AY, HSFY, PRY, RBMYL1, RPS4YS, SMCY, and XKRY) and AZFc contains five such genes (BPY2, CDY1, CSPG4LY, DAZ, and GOLGA2LY), which are all transcribed in testicular tissue and, are all candidates for some function in human spermatogenesis [5]
Microdeletions were detected in 12 patients (12/160 patients = 7.5%) and were most frequently limited to the AZFc region alone (7 patients: cases 1, 2, 4, 8, 9, 10, and = 58.3%), followed by microdeletions in the combined AZFb and AZFc regions (3 patients: cases 5, 6, and 7 = 25%), in the AZFa region alone (1 patient: case 3 = 8.3%) and in the combined AZFa, AZFb, and AZFc regions (1 patient: case = 8.3%)
Summary
The incidence of somatic chromosomal anomalies in the infertile male population is approximately 10% and this frequency increases as the sperm concentration in ejaculate decreases [2]. These anomalies may be numerical or structural and involve sex chromosomes (e.g., 47,XXY) or autosomes (e.g., balanced Robertsonian translocations). The reported incidence of AZF microdeletions in non-obstructive azoospermia or severe idiopathic oligospermia varies widely due to the selection criteria used. After the Klinefelter syndrome, Y chromosomal microdeletions are the most frequent genetic cause of male infertility [3] Analysis of these deletions demonstrates that at least three loci (AZFa, AZFb, and AZFc) are required for normal spermatogenesis [4]. Microdeletions of the AZF genes are caused by intrachromosomal recombination events between large homologous repetitive sequence blocks, and it is currently accepted that AZFb contains eight protein-coding genes (CDY2, EIF1AY, HSFY, PRY, RBMYL1, RPS4YS, SMCY, and XKRY) and AZFc contains five such genes (BPY2, CDY1, CSPG4LY, DAZ, and GOLGA2LY), which are all transcribed in testicular tissue and, are all candidates for some function in human spermatogenesis [5]
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