ABCMdb

PMID: 25122143

Audrezet MP, Munck A, Scotet V, Claustres M, Roussey M, Delmas D, Ferec C, Desgeorges M
Comprehensive CFTR gene analysis of the French cystic fibrosis screened newborn cohort: implications for diagnosis, genetic counseling, and mutation-specific therapy.
Genet Med. 2015 Feb;17(2):108-16. doi: 10.1038/gim.2014.113. Epub 2014 Aug 14., [PubMed]

Sentences

No. Mutations Sentence Comment

53 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Gly85Glu ABCC7 p.Gly85Glu ABCC7 p.Tyr122* ABCC7 p.Tyr1092* ABCC7 p.Trp846* ABCC7 p.Glu60* Because only a limited number of functional studies have assessed the pathogenicity of variants, mutations have been classified in previous studies according to their disease-causing potential.16,22,23 Based on the recommendations and data from these studies (UMD-CFTR-France),24 variants were classified into four groups: A, CF-causing; B, associated with CFTR-RDs; C, no clinical consequences; and D, unknown or Table 1ߒ Allelic frequencies of CF30-kit mutations, identified in neonates with CF, and correspondence between traditional mutation nomenclature and that on the Human Genome Variation Society website Frequency (F) % Mutation Legacy mutation nomenclature Number of alleles/2,320 % of alleles/2,320 Cumulative % ࣙ5 p.Phe508del F508del 1,560 67.24 67.24 p.Gly542* G542X 113 3.19 10.51 p.Asn1303Lys N1303K 81 1.98 c.1585-1G>A 1717-1G>A 48 1.47 1.00ࣙFࣙ4.99 c.2657ߙ+ߙ5G>A 2789ߙ+ߙ5G>A 37 1.42 p.Arg553* R553X 36 1.29 p.Gly551Asp G551D 31 1.16 p.Tyr122* Y122X 26 0.97 6.86 c.2988ߙ+ߙ1G>A 3120ߙ+ߙ1G>A 22 0.82 c.579ߙ+ߙ1G>T 711ߙ+ߙ1G>T 18 0.67 p.Ile507del I507del 17 0.63 c.3140-26A>G 3272-26A>G 16 0.59 0.40ࣙFࣙ0.99 p.Arg347Pro R347P 15 0.56 p.Arg1162* R1162X 15 0.56 p.Trp1282* W1282X 14 0.52 p.Tyr1092* Y1092X 13 0.48 c.2051_2052delinsG 2183AA>G 12 0.45 c.3528delC 3659delC 11 0.41 c.1680-886A>G 1811ߙ+ߙ1.6kbA>G 9 0.39 p.Gly85Glu G85E 8 0.34 3.06 p.Ser1251Asn S1251N 7 0.30 p.Arg334Trp R334W 7 0.30 p.Arg117His R117H 7 0.30 0.1ࣙFࣙ0.39 p.Trp846* W846X 6 0.26 c.489ߙ+ߙ1G>T 621ߙ+ߙ1G>T 6 0.26 c.948delT 1078delT 5 0.22 p.Ala455Glu A455E 5 0.22 p.Glu60* E60X 4 0.17 c.262_263delTT 394delTT 4 0.17 c.3718-2477C>T 3849ߙ+ߙ10kbC>T 3 0.13 Total 2,034 87.67 87.67 Mutations are clustered into four groups of frequency intervals (>5%, 1-4.99%, 0.99-0.4%, and <0.4%). Login to comment 78 ABCC7 p.Arg117His ABCC7 p.Arg117His p.Arg117His (R117H) was the second most frequent alteration in the cohort as a whole (7.8% of patients; n = 105). Login to comment 81 ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Ser945Leu ABCC7 p.Ser945Leu ABCC7 p.Asp1152His ABCC7 p.Asp1152His Some molecular defects that could belong to either the CF-causing group or the CFTR-related disorders group (group A/B) were reported in patients presenting a broad spectrum of phenotypes from classic CF to mild monosymptomatic presentations.16 These are four missense mutations (p.Leu206Trp (L206W), p.Arg347His (R347H), p.Asp1152His (D1152H), and p.Ser945Leu (S945L)) and three splice mutations (c.2657+5G>A (2789+5G>A), c.3718-2477C>T (3849+10kbC>T), and c.1210-34TG(13);1210-12T(5) (TG13T5)). Login to comment 91 ABCC7 p.Asn1303Lys A total of 577 CF patients (49.74%) were homozygous for mutations identified by the CF30 kit, including p.Phe508del (n = 552, 47.58%), p.Gly542* (n = 5, 0.43%), and p.Asn1303Lys Figure 1ߒ French cystic fibrosis (CF) newborn screening (NBS) algorithm. Login to comment 121 ABCC7 p.Tyr122* The mutation spectrum in neonates with CF diagnosed through NBS is consistent with the previously reported spectrum in patients with CF diagnosed based on clinical symptoms.12 The percentage of the main mutations was similar (Figure 3); however, there were significantly higher rates of specific mutations, including p.Tyr122* (Y122X) in CF patients from the R&#e9;union Island (prevalence, 0.97 vs. 0.16%; P < 10-6 ) and c.2988+1G>A (3120+1G>A) (prevalence, 0.82 vs. 0.09%; P < 10-6 ) in patients of African origin. Login to comment 139 ABCC7 p.Arg117His Whether these cases, representing up to 13.66% of our overall cohort, half of which carry a p.Arg117His mutation, might benefit from NBS is highly questionable. Login to comment 140 ABCC7 p.Arg117His Recently, Thauvin et al.31 assessed individuals carrying a p.Arg117His mutation and a CF-causing mutation, showing classic CF penetrance of 0.03% and severe CF penetrance in adulthood of 0.06%. Login to comment 141 ABCC7 p.Arg117His Considering that the aim of NBS is early diagnosis of classic forms of CF, their findings provide a strong argument for removing the p.Arg117His mutation from the CFTR NBS mutation panel. Login to comment 144 ABCC7 p.Gly551Asp Depending on their functional impact, new therapeutic approaches have emerged, with mutation-specific treatments that target specific gene defects.32 Potentially active agents have been identified and analyzed, resulting in several new compounds and, in one case (VX-770 for the p.Gly551Asp mutation),33 in a license in the United States and Europe. Login to comment