Background A growing number of non-coding regulatory mutations are being
identified in congenital disease. Very recently also some exons of protein
coding genes have been identified to act as tissue specific enhancer elements
and were therefore termed exonic enhancers or “eExons”. Methods We screened a
cohort of 134 unrelated families with split-hand/split-foot malformation
(SHFM) with high resolution array CGH for CNVs with regulatory potential.
Results In three families with an autosomal dominant non-syndromic SHFM
phenotype we detected microdeletions encompassing the exonic enhancer (eExons)
15 and 17 of DYNC1I1. In a fourth family, who had hearing loss in addition to
SHFM, we found a larger deletion of 510 kb including the eExons of DYNC1I1
and, in addition, the human brain enhancer hs1642. Exons 15 and 17 of DYNC1I1
are known to act as tissue specific limb enhancers of DLX5/6, two genes that
have been shown to be associated with SHFM in mice. In our cohort of 134
unrelated families with SHFM, deletions of the eExons of DYNC1I1 account for
approximately 3% of the cases, while 17p13.3 duplications were identified in
13% of the families, 10q24 duplications in 12%, and TP63 mutations were
detected in 4%. Conclusions We reduce the minimal critical region for SHFM1 to
78 kb. Hearing loss, however, appears to be associated with deletions of a
more telomeric region encompassing the brain enhancer element hs1642. Thus,
SHFM1 as well as hearing loss at the same locus are caused by deletion of
regulatory elements. Deletions of the exons with regulatory potential of
DYNC1I1 are an example of the emerging role of exonic enhancer elements and
their implications in congenital malformation syndromes