CBAVD G551D Mutation

Question

During a diagnostic work-up for azoospermia I (32 years old) was diagnosed with a heterozygous G551D mutation.

If this is indeed CBAVD (congenital bilateral absence of the vas deferens), shouldn’t there be a further (undetected) mutation? I have been having slight digestive problems for a year now. Would an appointment at a CF clinic make sense?

Many thanks for your answer.

Answer

Dear questioner,

I would like to give you three answers to your two questions:

1. Would an appointment in the CF clinic make sense?
No. If you are experiencing slight digestive problems at the age of 31, this is no reason to go to a specialized CF clinic – not even in combination with a genetic result of G551D heterozygousity and a clinical diagnosis of azoospermia. Digestive problems can have various causes and it would make sense to first get a differential diagnosis from a GP.

2. What are the causes of azoospermia?
Azoospermia, too, has many causes: known genetic factors include, for example, so-called "azoospermia factors" (AZF for short) that are coded on the Y chromosome. There are also different types of azoospermia, e.g. obstructive azoospermia (where, in contrast to CBAVD, the channels are “only” obstructed, but anatomically still present). The best specialists for this differential diagnosis are andrologists at specialized centres. The following two statements are true for patients with azoospermia and genetic analyses: First, patients with azoospermia have mutations of the CFTR gene or of the AZF locus more frequently than healthy people do. Second, with many azoospermia patients, no genetic causes for the disease can be found – it is assumed that environmental causes play a significant role. Common examples include dye in the clothes, pesticides in the food chain, additives in the omnipresent plastic materials, etc.; in short: an endless list of chemicals we cannot elude in our industrialized society (source: Statement of the European Society of Human Genetics, European Journal of Human Genetics (2006) 14, 588–645).

3. Does there have to be an undetected mutation besides G551D in CBAVD?
Yes, this is true for the majority of cases: patients with CBAVD carry two mutations of the CFTR gene. The current consensus paper of the professional association from the year 2011 (Journal of Cystic Fibrosis, Volume 10 Suppl 2 (2011) S86–S102) says the following on the topic: CBAVD only concerns 3% of men suffering from infertility. In 70-90% of the cases (the precise number depends on the geographic descent of the patient groups examined), CBAVD patients carry two variants in the CFTR gene. Here, the CFTR variant known as "IVS8 5T allele" is among the most frequent CBAVD-causing mutations. However, a test for the "IVS8 5T allele" is part of the standard CFTR gene test – I therefore assume that you are not carrying an "IVS8 5T allele." In order to be completely sure, specifically ask about the "IVS8 5T allele" if you do not have the precise test result of the human genetics lab.

Summary:
It is estimated that one in 20 healthy people carries CF-causing disorders, i.e. would get a result like yours if all of us were tested in a gene lab. The human genetic result "G551D heterozygous" is therefore very significant if you would like to become a father with medical help – then you and your partner will have to get consultation. For your personal health, you may ignore your G551D CFTR mutation just like all other gene carriers who are not aware of their CFTR variants do.

Kind regards
Frauke Stanke

17.01.2013

17.01.13
In general, if the diagnosis CBAVD is confirmed by a specialist, genetic analysis is performed to detect underlying CFTR-gene mutations. Males with CBAVD have either a CF-causing and a mild/variable or two mild/variable CFTR-mutations. Therefore, most of those males are otherwise asymptomatic and also remain it, like a "healthy gene carrier state". In some individuals however, mild manifestations as respiratory or pancreatic problems may occur later in life, so that males with CBAVD should be followed-up long-term for respiratory and gastrointestinal involvment.
D. d'Alquen