Categories of ΔF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics

Abstract

Cysti c fi br osi s (CF), the most common sever e autosomal r ecessi ve tr ai t among Caucasi ans, i s caused by mol ecul ar l esi ons i n the cysti c fi br osi s tr ansmembr ane conductance r egul ator gene (CFTR). The cour se of the mul ti -or gan di sease CF i s hi ghl y var i abl e, suggesti ng the i nfl uence of envi r onmental factor s and/or modul ati ng genes other than CFTR on the di sease phenotype. To evaluate the cause of CF disease variability, the European CF Twin and Sibling Study col l ected data on tw o cl i ni cal par ameter s most sensi ti ve for the cour se and pr ognosi s of CF, i e w ei ght pr edi cted for hei ght (w fh)% (r epr esentati ve for the nutr i ti onal status) and FEVPer c (r epr esentati ve for the pul monar y status) for a cohor t of 277 si bl i ng pai r s, 12 pai r s of di zygous tw i ns and 29 pai r s of monozygous tw i ns. Of these 318 CF tw i n and si b pai r s, 114 w er e r epor ted to be homozygous for the most fr equent CF di sease-causi ng l esi on, ∆F508. I ntr a-pai r di scor dance w as assessed by the i ntr a-pai r di ffer ences w i th w fh% and FEVPer c and by DELTA , a composi te par ameter defi ned by l i near combi nati on of w fh% and FEVPer c i n or der to descr i be di scor dance w i th r espect to the overall disease severity. Monozygous twins had a significantly lower DELTA than dizygous twins (P = 0.05) i ndi cati ng that CF di sease sever i ty i s modul ated by an i nher i ted component i n addi ti on to the CFTR gene i tsel f. Extr eme phenotypes ar e consi der ed to be mor e i nfor mati ve for the anal ysi s of any quanti tati ve tr ai t. Thus, w e ai med to quanti fy di sease sever i ty and i ntr a-pai r di scor dance i n or der to sel ect pai r s w i th the extr eme phenotypes DI S (di scor dant pati ent pai r s), CON + (concor dant and mi l dy affected pati ent pai r s) and CON -(concor dant and sever el y affected pati ent pairs). The algorithm reliably discriminated between pairs DIS, CON + and CON -among the cohor t of ∆F508 homozygotes. The sel ected pai r s fr om these categor i es demonstr ated non-over l appi ng pr oper ti es for w fh%, FEVPer c and the i ntr a-pai r di ffer ence of both par ameter s. Twin Research (2000) 3, 277-293. Keyw or ds: cysti c fi brosi s di sease severi ty, affected rel ati ve pai r, tw i n and si bl i ng study, extreme phenotypes, al gori thm based sel ecti on I ntr oducti on Cysti c fi brosi s (CF) i s know n as the most common severe autosomal recessi ve di sease w i thi n the Caucasi an popul ati on, exhi bi ti ng an i nci dence of 1 i n 2500 bi rths.1 The symptoms of the di sorder are caused by an i mpai red functi on of exocri ne gl ands i n many organs, but major mani festati ons i nvol ve the respi ratory and the gastroi ntesti nal tracts.1 The di sease i s caused by mutati ons i n both chromosomal copi es of the cysti c fi brosi s transmembrane conductance regul ator (CFTR) gene. 2 The course of CF i s hi ghl y vari abl e w hen compari ng unrel ated pati ents w i th i denti cal CFTR mutati on genotypes, 3,4 o...

Transmission ratio distortion and maternal effects confound the analysis of modulators of cystic fibrosis disease severity on 19q13

“…The European CF twin and sibling study patient panel As described in detail previously, 6 we have recruited CF twin and sibling pairs and their parents from central Europe. For the identification of CF modulators, F508del-CFTR homozygous dizygous patient pairs with concordant mild disease, concordant severe disease and discordant pairs were selected.…”

“…For the identification of CF modulators, F508del-CFTR homozygous dizygous patient pairs with concordant mild disease, concordant severe disease and discordant pairs were selected. 6 In total, 37 nuclear families with contrasting phenotypes were enrolled for genotyping whereby parental DNA was obtained in 32 families. 8 Unrelated F508del homozygotes stratified for year of birth The long-term prognosis and survival has improved considerably over the last decades.…”

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

“…The latter comparison asks whether CF intrapair discordance is modified by variants in the candidate gene mediated through interaction partners encoded in trans: 26,31,39 two sibs of a discordant pair mostly share their alleles at the investigated loci while their phenotype is dissimilar by designation. 40 Consequently, their discordant phenotype cannot be based on the investigated sequence alone if these are shared by two discordant sibs. Instead, an observed allelic association with the discordant phenotype implies a regulatory element encoded in cis -not present among concordant chromosomes -which can be targeted by a DNA-binding protein encoded in trans or alternatively, any similar gene-gene interaction on the transcriptional or post-transcriptional level.…”

Strain-dependent pulmonary gene expression profiles of a cystic fibrosis mouse model

“…Indeed, the subset of ϳ50% of CF patients who are homozygous for the ⌬F508 mutation and who exhibit variable CF symptoms provides evidence that non-CFTR factors are involved in the development of this disease (22). The increased concordance of CF disease severity in monozygotic twins compared with dizygotic twins (20,27) indicates that some of these non-CFTR factors are genetic (modifier genes). In support of this, clinical investigations (21) have identified associations between the genotypes of physiological candidate genes and the severity of CF lung disease.…”