New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot and double outlet right ventricle.
Conotruncal defects (CTDs) represent 15-20% of all congenital heart defects. Mutations in a number of genes have been associated with CTD in humans and animal models. We investigated the occurrence and the prevalence of GATA4, NKX2.5, ZFPM2/FOG2, GDF1, and ISLET1 gene mutations in a large cohort of individuals with CTD, including tetralogy of Fallot with or without pulmonary atresia (TOF, 178 patients), double outlet right ventricle (DORV, 13 patients), and truncus arteriosus (11 patients). Denaturing high-performance liquid chromatography (DHPLC) analysis followed by bidirectional sequencing disclosed no putative pathogenic mutation in GATA4, ISLET1, and GDF1 genes. Two novel (Ile227Val, Met544Ile) and one previously reported (Glu30Gly) possibly pathogenic missense variants were identified in the ZFPM2/FOG2 gene in 3 sporadic patients of 202 (1.5%) with CTD, including 1 of 178 (0.6%) with TOF and 2 of 13 (15.4%) with DORV. Mutation analysis also detected one known missense change (Arg25Cys) in NKX2.5 gene in two (1.1%) sporadic patients with TOF. These sequence alterations were found to be absent in 500 population-matched controls. In conclusion, the present results (i) indicate and confirm that mutations in the GATA4, GDF1, and ISLET1 genes are not major determinants in the pathogenesis of TOF, (ii) provide supportive evidence of an association between ZFPM2/FOG2 gene and TOF/DORV, and (iii) provide additional examples of the possible contribution of the Arg25Cys change in the NKX2.5 to a small number of TOF cases.
De Luca
Alessandro
A
CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Rome, Italy. a.deluca@css-mendel.it
Sarkozy
A
A
Ferese
R
R
Consoli
F
F
Lepri
F
F
Dentici
M L
ML
Vergara
P
P
De Zorzi
A
A
Versacci
P
P
Digilio
M C
MC
Marino
B
B
Dallapiccola
B
B
D001483:Base Sequence; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004310:Double Outlet Right Ventricle / Q000235:genetics*; D050991:GATA4 Transcription Factor / Q000235:genetics; D055452:Growth Differentiation Factor 1 / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D013771:Tetralogy of Fallot / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C525977:GDF1 protein, human; D055452:Growth Differentiation Factor 1; D014157:Transcription Factors; C117427:ZFPM2 protein, human