The incidence and possible relevance of Y-linked microdeletions in babies born after intracytoplasmic sperm injection and their infertile fathers

Abstract

Microdeletions linked to deletion intervals 5 and 6 of the Y chromosome have been associated with male factor infertility. Members from at least two gene families lie in the region containing azoospermia factor (AZF), namely YRRM and DAZ. With the advent of intracytoplasmic sperm injection (ICSI), it is possible for men with severe male factor infertility to produce a child. The genetic consequences of such a procedure have been questioned. This report describes the first study of a population (32 couples) of infertile fathers and their sons born after ICSI. The objectives were firstly to determine the incidence and map location of Y chromosome microdeletions and to compare the frequencies with other population studies involving severe male factor infertility, and secondly to formulate a working hypothesis concerning developmental aetiology of Y chromosome microdeletions. The incidence of microdeletions in the ICSI population was shown to be 9.4% (within the range 9-18% reported for populations of severe male factor infertility patients). Microdeletions in two out of three affected father/son pairs mapped in the region between AZFb and AZFc and the third involved a large microdeletion in AZFb and AZFc. Of three affected father/son pairs, microdeletions were detected in the blood of one infertile propositus father and three babies. Assuming that the gonomes of the ICSI-derived babies are direct reflections of those of their fathers germ lines, it is possible that two of three infertile fathers were mosaic for intact Y and microdeleted Y chromosomes. In such cases, the developmental aetiology of the microdeletion may be due to a de-novo microdeletion arising as a post-zygotic mitotic error in the infertile propositus father, thus producing a mosaic individual who may or may not transmit the deletion to his ICSI-derived sons depending on the extent of primordial germ cell mosaicism. In one of three affected fathers, the microdeletion detected in his blood was also detected in his ICSI-derived son. In this case the de-novo event giving rise to the microdeletion may have occurred due to a post- (or pre-) meiotic error in the germ line of this father's normally fertile father (i.e. the ICSI-derived baby's grandfather).

Sperm Cryopreservation in Male Infertility Due to Genetic Disorders

“…Until now only 17 male and 18 female ICSI babies born from fathers affected by Yq microdeletions have been reported (Kent-First et al 1996;Mulhall et al 1997;Jiang et al 1999;Kamischke et al 1999;Kleiman et al 1999;Cram et al 2000;van Golde et al 2001;Peterlin et al 2002;Oates et al 2002). It appears that the children are phenotypically normal, except for one son born with pulmonary atresia and a hypoplastic right ventricle (Page et al 1999) and no ambiguous genitalia or Turner syndrome have been observed among them.…”

Report on optimal evaluation of the infertile male

“…Sons of individuals with such a microdeletion would inherit the microdeletion and consequently may be infertile (26). Although a microdeletion of the Y chromosome is not thought to be associated with other health problems, few data exist on the phenotypes of the sons of fathers with such genetic abnormalities.…”

Report on evaluation of the azoospermic male

“…Sons of individuals with a Y-chromosome microdeletion will inherit the microdeletion and may consequently be infertile (18). Although a microdeletion of the Y chromosome is not thought to be associated with other health problems, few data exist on the phenotypes of the sons of fathers with such genetic abnormalities.…”