Exome sequencing identifies a c.148-1G>C mutation of TBX5 in a Holt-Oram family with unusual genotype-phenotype correlations.

BACKGROUND/AIMS Congenital heart defects (CHD) can occur with upper limbs deformities. Holt-Oram syndrome is the main type of heart-hand syndromes, characterized by upper limb radial ray malformations, CHD and/or conduction abnormalities. Mutations of the TBX5 gene, most of which are found within the T-box domain, are one cause of the disease. We aimed to find the cause of the disease in a family with two children exhibiting symptoms of Holt-Oram syndrome while the parents tend to be normal. METHODS Chromosomal microarray analysis and exome sequencing were applied in the proband segments bearing the specific mutation and single nucleotide variants (SNVs) suspected of being involved in the disease were analyzed by polymerase chain reaction and direct sequencing. RESULTS A splice acceptor site mutation c.148-1G>C of TBX5 was detected in both the father and the proband. The mutation may result in an aberrant transcript which will most probably undergo nonsense-mediated decay (NMD) system resulting in haploinsufficiency of TBX5 protein. In the meantime, 3 candidated SNVs were detected. CONCLUSIONS c.148-1G>C of TBX5 should be the pathogenic cause of the disease in this family. Works have been done to find a possible explanation of the unusual genotype-phenotype correlations in this family and further studies are still needed.