State of the Art for Genetic Testing of Infertile Men

Abstract

Intracytoplasmic sperm injection (ICSI) now provides fertility in many cases of severe idiopathic spermatogenic failure and obstructive azoospermia. Genetic causes must be sought by systematic evaluation of infertile men and affected couples informed about the implications of such diagnoses for assisted reproductive technology outcome and their potential offspring. This review discusses established and emerging genetic disorders related to fertility practice. Chromosomal anomalies are found in about 7% men with idiopathic spermatogenic failure, predominantly numerical/structural in azoospermic men and translocations/inversions in oligospermic men. Routine karyotyping of men with sperm densities less than 10 million/ml, even in the absence of other clinical presentations, is recommended because infertility is associated with higher rates of aneuploidy in ejaculated or testicular sperm and increased chromosomal defects in ICSI offspring. The long arm of the Y chromosome microdeletions are the most common recognized genetic cause of infertility and are found in about 4% men with sperm densities less than 5 million/ml. Routine testing using strict quality assurance procedures is recommended. Azoospermia factor (AZF)-c deletions, the most common form of the long arm of the Y chromosome microdeletions, are usually associated with low levels of sperm in the ejaculate or in testis biopsies, whereas men with AZFa or AZFb+c deletions usually produce no testicular sperm. When AZF-deleted sperm are available and used for ICSI, fertility defects in male offspring seem inevitable. Bilateral congenital absence of the vas is associated with heterozygosity for cystic fibrosis transmembrane receptor mutations making routine gene screening and genetic counseling of the couple essential. Testing for less common genetic associations/defects linked with different reproductive dysfunction may be applicable to specific patients but have not entered routine practice.

Y chromosome AZFc microdeletion may not affect the outcomes of ICSI for infertile males with fresh ejaculated sperm

“…The treatment outcomes of infertile men who suffered from Y chromosome microdeletion has been controversial. Some studies have demonstrated comparable treatment outcomes in patients with or without Y chromosome microdeletions [22,23]. However, other studies showed different outcomes, particularly in fertilization rate and quality of embryos between these two groups.…”

Meiotic recombination and male infertility: from basic science to clinical reality?

“…Karyotype analysis is recommended and routinely performed for couples who experience repeated spontaneous abortions and men with oligozoospermia, even in the absence of other clinical presentations. Karyotype abnormalities, be they structural or numerical in nature, are observed in 0.4% of liveborns, but infertility is associated with increased levels of chromosome aberrations 5 affecting 2% of males presenting with fertility problems; 6% of oligozoospermic and 14% of non-obstructive azoospermic (NOA) males. 6 In fact, the most common genetically identifiable cause of male factor infertility is Klinefelter syndrome, which is a condition that arises as the result of an additional sex chromosome (47,XXY) in the somatic karyotype.…”

Uso da FISH em mucosa oral para investigação de mosaicismo com linhagem 45,X: estudo com homens saudáveis e pacientes com distúrbios da diferenciação do sexo

“…Revisões recentes sobre o assunto não chegam a mencionar o cariótipo 45,X/46,XY como um dos possíveis achados (21), embora este também possa ser encontrado. Assim, ao ser solicitado o exame de cariótipo raramente essa é uma hipótese que já esteja sendo considerada, e também raramente está prevista a necessidade de pesquisar mosaicismo por FISH.…”