exon 13 sequence variant D727Y

Question

Hello,
in my daughter, the mutation exon 13 D727Y has been diagnosed heterozygously and in intron 8 the 7T-allel homozygously. Does that have any consequences? There are mutations however, which are not known already and not detectable. Is this CF or not? I would very much like to know if she suffers from CF or not in order to initiate a therapy because this is very important in CF.

Her clinical data:

3 positive sweat test conductivity measurements, underweight, constant airway-infections, gastro-intestinal infections, problems of digestion, extreme transpiration, curved nails, increased bile acids, thorax x-ray minimal suspicious, genetic testing negative, complete gene test exon 13 D727Y, bronchitis, several times scarlet fever, problems with the kidneys, 1.11 cm and 15.1 kg, age 6.
She has been tested on: celiac disease, food intolerance, allergies, anorexia, dermatitis, dysfunction, dysplasias, dehydration, deprivation, cholestase-fucosidose,g luose 6 phosphat dehydrogenase, glykogenose typ1, hypogammaglobulinaemia, klinefelter syndrome, long-term-pge1 infusion, mauriac syndrome, mucopolysaccharidose type 1, protein deficiency nutrition, pseudohypoaldosteronism, short stature. diabetes, nephrose, adrenal gland insufficiency, hypothyreosis. All these investigations have been negative.

Answer

Hello,
the D727Y is not a common known sequence variation, it is not either mentioned in the Toronto-CF-mutation-data bank. That means it has probably been detected by instance during the analysis of the whole CFTR-gene and it has not been specifically looked for it. As it has not been described before so far, it is not known, if it influences the function of the CFTR-protein. As long as its influence on the gene-product is not investigated, it has to be titled as a sequence variant, which could be benign or illness causing (pathogenic).
As long as there is no second mutation, however, that means as long as the D727Y-mutation is present in a heterozygous state, it has no impact on the health, irrespective if it is pathogenic or not. The T7-allele is the most common one in the population and does not cause CF.
In case the suspicion of CF will still be there due to the clinical picture and in case of lacking detection of a second mutation/variant after analysis of the whole coding sequence of the CFTR-gene, a transcription-analysis from nasal epithelium should probably be considered, in order to detect changes of sequences which could impair the correct splicing.
Of course one should expect to bring everything to one point with such broad diagnostic measures. This is unfortunately not true, because very often we have to admit, that it is not possible to name the problem. This is however at the moment probably anyway an overrated phenomenon. What is the difference for the single child, in case we could say, that it deals with a mutation of the CFTR-gene? We still treat anyway only the symptoms, that means we are treating according to the problems, if there is an infection of the lung then it has to be treated, in case there are the typical germs of CF-patients, they are treated accordingly. We do this independent of the certified diagnose.
Of course we – the doctors as well as the parents – want a diagnose, more important is however an optimal therapy and the latter is (still) independent of the genetic findings.
I know that the uncertainty is hard to bear, but I find it comforting that one can say: everything that helps for CF can also be used if there is a clinical picture similar to CF, without being able to name the diagnose exactly. I hope to have helped you further with my answer and send you best regards,

Prof. Sabina Gallati und Prof. Dr. TOF Wagner

16.09.2010

16.09.10 Altogether 4 Q/As have been posed on this topic by the same questioner. I summerized them all under this single one. D. d'Alquen