Progressive AV-block and anomalous venous return among cardiac anomalies associated with two novel missense mutations in the CSX/NKX2-5 gene.
Non-syndromic cardiac septation defects are common, yet the causative factors remain largely uncharacterised. Septation defects are an integral part of many syndromes, some of which are associated with chromosomal alterations. For the majority, the physiopathogenesis is believed to be multi-factorial, hindering the identification of causative factors. Ten mutations in the gene encoding the transcription factor CSX/NKX2-5 have been described in individuals with ASD and/or atrioventricular conduction defects. In addition, several other cardiac abnormalities were observed, yet the mildest forms are reminiscent of non-syndromic septation defects. The CSX/NKX2-5 gene is thus a good candidate for various cardiopathies. We have collected two families with inherited predisposition to cardiac abnormalities. Some members of the families presented ASD and AV block. In both families a novel CSX/NKX2-5 mutation was identified in the homeodomain. Variable expressivity in the phenotype was observed in both families. Importantly, mutation carriers did not present any symptoms at young age. In addition, anomalous venous return, a phenotype not previously associated to CSX/NKX2-5 mutations, was observed in one of the families. We also screened the CSX/NKX2-5 gene in sporadic and familial cases of other cardiopathies. As additional mutations were not found, substitutions in CSX/NKX2-5 gene seem to be a rare cause of cardiopathies without conduction defect.
Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Brussels, Belgium.
Ilse
I
Gutierrez-Roelens
Thierry
T
Sluysmans
Marc
M
Gewillig
Koen
K
Devriendt
Miikka
M
Vikkula
D000595:Amino Acid Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004452:Echocardiography; D005192:Family Health; D005260:Female; D006327:Heart Block / Q000150:complications* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics*; D014684:Venae Cavae / Q000002:abnormalities*
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors; D004247:DNA