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D1152H and G85E

Question
Hello, my son (5 months plus) has inherited the D1152H and G85E mutations. His sweat test at 14 days old came back borderline at 33. His first two fecal elastase tests came back borderline, but his most recent test came back normal. Overall he has been healthy thus far. Any info on these two mutations besides what is available on the CFTR1/CFTR2 websites? I have read that D1152H is a class IV mutation, but I have seen G85E characterized as class II, III or IV on different websites. Is there a possibility for Kalydeco working on either mutation? Thanks for any info. This is a wonderful site! (I apologize I entered this question anonymously first).
Answer
Dear Parent
Thank you for your question concerning your son’s genetics D1152H and G85E
Hello, my son (5 months plus) has inherited the D1152H and G85E mutations. His sweat test at 14 days old came back borderline at 33. His first two fecal elastase tests came back borderline, but his most recent test came back normal. Overall he has been healthy thus far. Any info on these two mutations besides what is available on the CFTR1/CFTR2 websites? I have read that D1152H is a class IV mutation, but I have seen G85E characterized as class II, III or IV on different websites. Is there a possibility for Kalydeco working on either mutation? Thanks for any info. This is a wonderful site! (I apologize I entered this question anonymously first).

G85E is an uncommon mutation seen in approximately 0.2% of the CF population worldwide but it has an increased incidence in those of Mediterranean decent. It is a Class II mis-sense mutation with the substitution of glycine with glutamic acid, leading to a trafficking defect. It does appear to have a variable presentation with some patients being pancreatic sufficient, sweat chlorides can be lower and rates of lung disease are variable. I refer you to an excellent paper in the European Respiratory Journal by Decaestecker et al which collected extensive data on 68 patients either homozygous/compound heterozygous for G85E.
D1152H is a Class IV mutation and has a higher incident in Azs Jews again has been noted to have a variable presentation, people may be pancreatic sufficient, lung disease is variable in its severity and pancreatitis in later years seems to be more prevalent.

To date Ivacaftor studies have looked mostly at its effects on G551D (Class III) mutation for which it use to treat this group of patients has been approved. There are several studies ongoing/pending looking at the effects of Ivacaftor on other mutations. There is one looking at its effect on R117H(Class IV) mutation. One study is looking at Ivacaftor in subjects with CF and a non-G551D gating mutation the 9 mutations are listed but neither D1152H or G85E are included in these studies. There is a study pending on the short term effects of Ivacaftor in non-G551D CF patients with signs of residual CFTR function. This study has not started recruiting yet and mutations to be included have not been specified. Ivacaftor is also being studied in combination with lumacaftor in subjects with F508del( Class II) mutation.

So at present Ivacaftor’s use remains only for those with G551D and any widening of its scope of use will depend on further clinical trials.

1. Eur Respir J, 2004, May;23(5):679-84.Genotype/phenotype correlation of G85E mutation in a large cohort of CF patients Decaestecker K, Decaestecker E, Castellani C, Jaspers M, Cuppens H, De Boeck K

2. Pediatrics 1997 Sep;100(3):E5.A missense cystic fibrosis transmembrane conductance regulator mutation with variable phenotype.
Kerem E, Nissim-Rafinia M, Argaman Z, Augarten A, Bentur L, Klar A, Yahav Y, Szeinberg A, Hiba O, Branski D, Corey M, Kerem B.

3. clinicaltrials.gov

4. 2010 Apr;77(4):355-64. Epub 2009 Oct 15.Non-classic cystic fibrosis associated with D1152H CFTR mutation.Burgel PR, Fajac I, Hubert D, Grenet D, Stremler N, Roussey M, Siret D, Languepin J, Mely L, Fanton A, Labbé A, Domblides P, Vic P, Dagorne M, Reynaud-Gaubert M, Counil F, Varaigne F, Bienvenu T, Bellis G, Dusser D.

5. 2006 Mar;41(3):250-4.Cystic fibrosis mutations with widely variable phenotype: the D1152H example.Mussaffi H, Prais D, Mei-Zahav M, Blau H.

30.07.2013
The answer is edited by: Laura Jenkins