Introduction: Homozygous damaging mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the primary cause of congenital bilateral absence of the vas deferens (CBAVD). In addition, a high incidence of heterozygous damaging mutations in CFTR have long been implicated in infertility in non-CBAVD males. In the present study we sought to identify novel carrier mutations significantly associated with male infertility from a panel of 62 genes causing common congenital disorders including cystic fibrosis.
Methods: Over the most recent 18-month period, our center performed expanded carrier screening on 165 men receiving a variety of urological treatments including treatment for male infertility, hypogonadism, erectile dysfunction, hematuria, Peyronie's disease, scrotal mass, varicocele, vasectomy, and vasovasostomy. Of these 165 men, 59 were being treated for infertility with full semen analysis reports confirming abnormal semen parameters in 72% of these men (azoospermia, oligozoospermia, asthenozoospermia, or oligoasthenozoospermia).
Results: Of the 62 genes tested in 165 men, heterozygous carrier mutations were detected in 12 genes in 57 men (Table 1). No published association between these gene mutations and male infertility could be found for any of the genes except for CFTR. For CFTR, we found a significant 2.3-fold (P <0.05) increase in the number of infertile men with CFTR mutations (9 out of 59 men, or 15.3% of men) relative to the number of other men (men treated for other conditions) with CFTR mutations (7 out of 106 men, or 6.6% of men). None of the azoospermic men with CFTR mutations had congenital bilateral absence of the vas deferens.
Conclusions: Our results are consistent with, but more robust than those of previous studies due to the increased number of mutations tested for in our study. CFTR function has been shown in the epididymis, CFTR protein is present in developing germ cells and sperm, and its function contributes to events required for capacitation in the female reproductive tract. In conclusion, these data demonstrate that mutations in CFTR, even heterozygous mutations, are a likely cause of non-CBAVD male factor infertility in at least a subset of men affected by CFTR mutations.
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