Outcome of intracytoplasmic sperm injection for a couple in which the man is carrier of CFTR p.[R74W;V201M;D1270N] and p.P841R mutations and his spouse a heterozygous carrier of p.F508del mutation of the cystic fibrosis transmembrane conductance regulator gene

Genotype–phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles

“…In two other patients, the mutation was in trans with mutations with intrinsic residual CFTR function (ie, p.Asp579Gly and p.Asp1152His) that usually have a less severe clinical impact 42 43. They had CBAVD, and they compare with four patients previously described with the same complex allele in trans with mild mutations and CBAVD alone 16 17. The mean CFTR gating activity on NEC in three patients with CF that had in trans a class I–II mutation resulted 11.2% versus a mean of 6.2% (p<0.001) found in patients with CF and two class I–II mutations and 17.5% in three patients with CFTR-RD, confirming the higher residual activity of the p.[Arg74Trp;Val201Met;Asp1270Asn] mutated protein.…”

“…Indeed, the use of CFTR gene sequencing11 leads frequently to the detection of mutations for which it lacks a clear and univocal genotype–phenotype correlation12–14 also because the genetic background and the environment in which each patient lives contribute to the individual CF phenotype 12. Furthermore, the existence of complex alleles complicates even more genetic counselling 15 16. They result from the combination of two or more CFTR mutations in cis (ie, on the same allele) that usually act as a pathogenic mutation whereas each single mutation has only a minor or none effect.…”

“…They result from the combination of two or more CFTR mutations in cis (ie, on the same allele) that usually act as a pathogenic mutation whereas each single mutation has only a minor or none effect. Few subjects bearing the p.[Arg74Trp;Val201Met;Asp1270Asn],14 16 17 the p.[Ile148Thr;Ile1023_Val1024del],18 19 the p.[Arg117Leu;Leu997Phe]20–22 and the c.[1210-34TG[12];1210-12T[5];2930C>T]23 complex alleles were described so far with variable characteristics. However, a functional characterisation of the effect of these mutations was performed in a limited number of cases 17 23…”

Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R;H949L] allele

“…They are thought to affect the expression of the phenotype by modulating the effect of mutations: the combination of two missense mutations on the same allele has been described clinically either to improve ( Dork et al , 1991 ; Duarte et al , 1996 ) or worsen ( Hojo et al , 1998 ) the phenotype of CF patients with regard to the most common mutation alone. In some cases the double-mutant allele has been related with a severe phenotype ( Savov et al , 1995 ; Duarte et al , 1996 ), while in other cases complex alleles were not associated with classical form of CF ( Brugnon et al , 2004 ). Thus, further data are needed to clarify their functional role.…”

Functional analysis of the p.[Arg74Trp;Val201Met;Asp1270Asn]/p.Phe508del CFTR mutation genotype in human native colon

“…The corresponding clinical phenotype, however, is less clear. Individuals with p.Phe508del and p.[Arg74Trp;Val201Met;Asp1270Asn] in trans have been reported to be healthy (Brugnon et al, ) or to suffer from a CFTR‐related disorder (CFTR‐RD) or CF (Claustres et al, ).…”