Homozygosity of the cystic fibrosis (CF) gene allele IVS8-(5T) in a Tamil male with congenital bilateral absence of the vas deferens (CBAVD)

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(1)Molecular Human Reproduction vol.6 no.7 pp. 669–670, 2000. Letter to the Editor Homozygosity of the cystic fibrosis (CF) gene allele IVS8-(5T) in a Tamil male with congenital bilateral absence of the vas deferens (CBAVD) Dear Sir, We read with great interest the recent paper by Lissen et al. (1999), who reported on a high frequency of the intron 8 splice variant 5T (IVS8-(5T) within the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 20 Egyptian males with congenital bilateral absence of the vas deferens (CBAVD). They found homozygosity of the IVS8(5T) allele in five men and compound heterozygosity with an IVS8-(7T) allele in three men and with an IVS8-(9T) allele in one man. The authors conclude that the IVS8-(5T) variant is involved in many cases of CBAVD, even in populations with a low frequency of cystic fibrosis (CF). Recently, a 35 year old Tamil male with CBAVD was referred to our genetic counselling service. He is the fifth out of six children of healthy parents originating from two small neighbouring villages in Sri Lanka. Two out of three brothers fathered seven children. Family history was unremarkable for classical CF. In the patient, both kidneys were present and of normal size. Infertility investigations revealed normogonadotropic normogonadism and azoospermia. Ductus deferens was not palpable and testes volumes were 12 and 20 ml respectively. CBAVD was proven by bilateral operative exploration demonstrating spermatogenesis with a regular number of Leydig cells in both testes. For genetic evaluation, the 15 most common mutations of the CFTR gene in Caucasians were investigated by standard procedures (Chillon et al., 1995). Homozygosity for the 5T allele was found. Furthermore, homozygosity of three additionally tested highly polymorphic microsatellites located within intron 8 (IVS8CA) and intron 17 (IVS17BTA and IVS17BCA) of the CFTR gene was detected. The CFTR gene was cloned in 1989. Since then ⬎900 different mutations have been reported, most of them in populations of European origin (Cystic Fibrosis Mutation Data Base; http://www.genet.sickkids.on.ca/cftr). Prevalence and incidence of CF as well as the spectrum of mutations in nonCaucasian populations are not well known. So far, only 608 chromosomes from patients of the Middle East were registered in the International CF Data Base. Similar to Caucasian populations, ∆F508 is the most common detected mutation. Kabra et al. (1996) found the ∆F508 mutation in 14 out of 26 mutant chromosomes in Indian children with CF. From various East Asian countries only 10 patients with CF were investigated by molecular methods (Suwanjutha et al., 1998; Wagner et al., 1999). Three of the 20 investigated chromosomes carried the ∆F508 mutation. However, all these findings might be an © European Society of Human Reproduction and Embryology. ascertainment bias, as some Asian laboratories might not have the technical equipment to screen for rarer mutations. Male sterility is a common observation in classical CF. Anguiano et al. (1992) were the first to describe three men with compound heterozygosity for mutations in the CFTR gene and isolated CBAVD. Further studies revealed an association of CBAVD with mutations in the CFTR gene in up to 80% of affected men. Mostly a length polymorphism within intron 8 of the CFTR gene (IVS8-(5T)), resulting in reduced levels of mRNA and deletion of exon 9 due to alternative splicing was found. General frequency of the IVS8-(5T) polymorphism is low in Caucasians, whereas in men with isolated CBAVD this allele was found in up to 63% of investigated chromosomes in combination with a second CFTR mutation (Chillon et al., 1995). To our knowledge, apart from the report of Lissens et al. (1999) there are no systematic molecular studies for mutations in the CFTR gene in non-Caucasian men with isolated CBAVD. Furthermore, the IVS8-(5T) allele has so far not been reported in Asians. Thus, our observation is the first report of the IVS8-(5T) allele in a male of Asian origin with isolated CBAVD. Homozygosity of this allele and of three additional markers might be due to a common ancestor. Consanguinity was not known, but the parents of our patient are from neighbouring villages in Sri Lanka. Further family investigations were not possible as the parents as well as brothers and sisters are still living there. The findings in our patient and the ones by Lissens et al. (1999) are relevant for several aspects: (i) isolated CBAVD caused by mutations in the CFTR gene is not restricted to populations of European origin; (ii) the origin of our patient from Sri Lanka is a hint towards an independent occurrence of this mutation; (iii) knowledge of the presence and incidence of specific mutations in various populations is necessary for adequate genetic counselling of non-Caucasian males with infertility due to isolated CBAVD. In conclusion, we hope that the study of Lissens et al. (1999) as well as our observation of a Tamil male with isolated CBAVD associated with homozygosity of the IVS8-(5T) allele will stimulate investigations on CFTR mutations in populations other than Caucasians.. References Anguiano, A., Oates, R.D., Amos, J.A. et al. (1992) Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis. J. Am. Med. Assoc., 267, 1794–1797. Chillon, M., Casals, T., Mercier, B. et al. (1995) Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N. Engl J. Med., 332, 1475–1480. Kabra, M., Ghosh, M., Kabra, S.K. et al. (1996) Delta F508 molecular mutation in Indian children with cystic fibrosis. Indian. J. Med. Res., 104, 355–358.. 669.

(2) Letters to the Editor Lissens, W., Mahmoud, K.Z., El-Gindi, E. et al. (1999) Molecular analysis of the cystic fibrosis gene reveals a high frequency of the intron 8 splice variant 5T in Egyptian males with congenital bilateral absence of the vas deferens. Mol. Hum. Reprod., 5, 10–13. Suwanjutha, S., Huang, N.N., Wattanasirichaigoon, D. et al. (1998) Case report of a Thai male cystic fibrosis patient with the 1898⫹1G→T splicing mutation in the CFTR gene: A review of East Asian cases. Hum. Mutat., 12, 361. Wagner, J.A., Vassilakis, A., Yee, K. et al. (1999) Two novel mutations in a cystic fibrosis patient of Chinese origin. Hum. Genet., 104, 511–515.. S.Fokstuen, J.Balakrishnan, D.Kotzot, and M.Hergersberg1 Institut fu¨r Medizinische Genetik, Universita¨t Zu¨rich, Zu¨rich, Switzerland Ch.Hobi Klinik fu¨r Urologie, Kantonsspital St Gallen, St Gallen, Switzerland 1To. whom correspondence should be addressed at: Institut fu¨ r Medizinische Genetik, Universita¨ t Zu¨ rich, Ra¨ mistr. 74, CH8001 Zu¨ rich, Switzerland. E-mail: hergie@medgen.unizh.ch. 670.

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