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Recent studies have identified the genetic underpinnings of a growing number of diseases through targeted exome sequencing. However, this strategy ignores the large component of the genome that does not code for proteins, but is nonetheless biologically functional. To address the possible involvement of regulatory variation in congenital heart diseases (CHDs), we searched for regulatory mutations impacting the activity of  TBX5 , a dosage-dependent transcription factor with well-defined roles in the heart and limb development that has been associated with the Holt–Oram syndrome (heart–hand syndrome), a condition that affects 1/100 000 newborns. Using a combination of genomics, bioinformatics and mouse genetic engineering, we scanned ∼700 kb of the  TBX5  locus in search of  cis -regulatory elements. We uncovered three enhancers that collectively recapitulate the endogenous expression pattern of  TBX5  in the developing heart. We re-sequenced these enhancer elements in a cohort of non-syndromic patients with isolated atrial and/or ventricular septal defects, the predominant cardiac defects of the Holt–Oram syndrome, and identified a patient with a homozygous mutation in an enhancer ∼90 kb downstream of  TBX5 . Notably, we demonstrate that this single-base-pair mutation abrogates the ability of the enhancer to drive expression within the heart  in vivo  using both mouse and zebrafish transgenic models. Given the population-wide frequency of this variant, we estimate that 1/100 000 individuals would be homozygous for this variant, highlighting that a significant number of CHD associated with TBX5 dysfunction might arise from non-coding mutations in  TBX5  heart enhancers, effectively decoupling the heart and hand phenotypes of the Holt–Oram syndrome.

Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease