Genetic analysis of cardiac-specific transcription factors reveals novel insights into molecular causes of congenital heart disease.

Heart development is complex and requires the sequential and timely interplay of regulatory master proteins, notably several transcription factors. Germline mutations in the human transcription factor genes have been associated with congenital heart disease (CHD), but familial cases studied so far have different mutations. There is no strict genotype-phenotype correlation and mutations in transcription factor genes are rare in unrelated patients. Most cases of CHD come from unaffected family members. The study of archived, but morphologically well-characterized malformed hearts for DNA alterations provides important clues regarding cardiogenic transcription factor genes that would lead to loss-of-function of the protein. Identification of tissue-restricted multiple mutations and multiple haplotypes suggests that somatic mutation and mosaicism are linked to cardiac anomalies. Altogether, somatic mutations and genomic instability in the diseased cardiac tissues of patients with CHD provide a novel mechanism of disease.