Original article
Sperm FISH analysis in two healthy infertile brothers with t(15;18) unbalanced translocation: Implications for genetic counselling and reproductive management

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Abstract

Numerous studies have shown that balanced reciprocal or Robertsonian translocations and inversions are associated with reduced or absent sperm production. In contrast, a similar association has been rarely reported for unbalanced translocations. An unbalanced translocation, 45,XY,-15,der(18)t(15;18)(q11.2;q23), was found in two healthy infertile brothers who were referred to our hospital together with their partners for infertility. At least two routine semen analyses and karyotyping were done for each of the brothers. Sperm meiotic segregation was studied for both with a three-color FISH assay using locus-specific probes. Semen analyses showed a severe oligo-astheno-teratozoospermia with remarkably similar profiles in the two brothers. The unbalanced translocation had a deletion of 15pter-15q11.2 as well as a deletion of 18q23-18qter. The meiotic segregation was similar in the two brothers with a prevalence of alternate segregation mode. However, no phenotypic effect in the offspring can be expected only if the normal chromosomes 15 and 18 are transmitted to progeny. According to the sperm FISH results, the theoretical probability of this happening is about 25%. Based on the overall results, genetic and reproductive counselling was offered to both couples. Finally, both couples chose the alternative of donor insemination rather than preimplantation genetic diagnosis. The present study helps delineating a phenotypically silent CNV at the distal part of chromosome 18 long arm and illustrates the advantages of an integrated multidisciplinary genetic, reproductive and psychological approach to give the best possible assistance to couples who are faced with a complex and distressing genetic cause of infertility.

Introduction

Genetic causes including chromosomal aberrations and single gene mutations account for 10–15% of male infertility [11]. The frequency of constitutional chromosomal abnormalities is increased in infertile men by up to 13% in azoospermic men and 4% in oligozoospermic and/or asthenozoospermic patients [15]. In contrast, unbalanced translocations, which are associated with segmental aneusomies and which often result in mental retardation or multiple congenital anomalies, have not been reported in infertile patients. However, various chromosomal imbalances involving euchromatic regions have now been described in phenotypically normal individuals. Barber [2] has proposed dividing euchromatic anomalies into two categories: unbalanced chromosome abnormalities (UBCAs) such as deletions or duplications and euchromatic variants (EVs), mostly due to variation in copy number of pseudogenes.

We report here the first case, to our knowledge, of a t(15;18) unbalanced translocation that was found in two healthy brothers referred for infertility. The chromosomal anomaly was associated with a severely impaired production and quality of sperm. This unusual finding, which was distressing to both couples, clearly illustrates how the analytical process including the clinical examination, the molecular characterization of the chromosome rearrangement, the semen analysis and the analysis of meiotic segregation are essential for a multidisciplinary counselling to assist infertile couples in the best possible way in making their reproductive choices.

Section snippets

Case report

Propositus 1 was a 30 year-old Caucasian man. He was 75 kg in weight and 180 cm in height (+1 SD). He was referred together with his partner to the reproductive biology unit in Necker Hospital, West Paris University Hospital Group, by the gynaecologist because of a two year history of infertility with no obvious cause of infertility in the female partner. He was healthy without any dysmorphic features or impairment in cognition and had no particular medical history. We learnt that his brother was

Semen analysis

According to the protocol for an infertility check-up semen samples were collected in the two reproductive units from each brother after a recommended 3–5 days period of sexual abstinence. In each unit, semen analysis was performed following the WHO guidelines [32] except for sperm morphology, which was assessed using David’s modified classification [1].

Karyotype and FISH analysis

The brothers were referred for karyotyping by both reproductive units to the Cytogenetics Unit, Cochin Hospital, West Paris University Hospital

Semen analysis

Repeated semen analyses showed severe oligo-astheno-teratozoospermia in both brothers with remarkably similar profiles of the various semen characteristics assessed and, especially, an important exfoliation of immature germinal cells (Table 1).

Karyotype and FISH analysis

In each brother cytogenetic analysis revealed an abnormal karyotype with 45 chromosomes and an unbalanced translocation involving chromosome 15 and 18 confirmed by FISH analysis (Fig. 1A). The combined use of different probes indicated that the breakpoint

Discussion

The (15;18) unbalanced translocation found in these brothers has never been reported. It was detected by chance during a check-up for infertility in two healthy brothers with no unusual medical history. Despite the unavailability of parental blood samples (they refused further cytogenetic investigations), this translocation, which is characterized by a proximal deletion 15q and a terminal deletion 18q23, is likely to have been inherited since it is present in both brothers. Moreover, a

Conclusion

This study has led to the refinement of the size of the subtelomeric region of chromosome 18 long arm that is phenotypically silent in case of chromosomal imbalance. Furthermore, we illustrate the importance of sperm FISH studies and the advantages of an integrated multidisciplinary genetic, reproductive and psychological approach to give the best possible assistance to couples who are faced with a complex and distressing genetic cause of infertility.

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