Background: Truncus arteriosus (TA) accounts for ~1% of congenital heart defects (CHD). The etiology of isolated TA is largely unknown but when occurs as part of a syndrome, it is mostly associated with chromosome 22q11 deletion. Vice versa, the most common CHD associated with chromosome 22q11 deletion are conotruncal malformations. In this study we investigated the cause of multiple conotruncal malformations accompanied by athymia in two consanguineous families (Figure).
Methods and Results: Whole exome analysis revealed a homozygous deleterious mutation in the NKX2-6 gene. chr8: 23560417 InsT, c.453_454 insT, p.Lys152fs*0. The mutation segregated with the disease in the families (Figure) and was absent from in-house 78 exome analyses of patients of similar ethnicity. The mutation was also absent from the 2283 healthy individuals whose exome analysis results are available through the Exome Variant Server.
Conclusions: NKX2-6 encodes a homeobox-containing protein which is expressed in mouse embryo at E8.0-E9.5 at the caudal pharyngeal arches and the outflow tract. A single missense mutation was previously implicated in the etiology of familial isolated TA; however, null mice are entirely normal. The clear phenotype associated with a homozygous deleterious mutation in the present report, falls well within the spectrum of the cardiac defects seen in DiGeorge syndrome, is in agreement with NKX2-6 downstream location in the TBX1 signaling pathway and confirms NKX2-6 role in human cardiogenesis.
