RT Journal Article
SR Electronic
T1 Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for <em>DYNC1I1</em> exonic enhancers of <em>DLX5/6</em> expression in humans
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 264
OP 267
DO 10.1136/jmedgenet-2013-102142
VO 51
IS 4
A1 Hana Lango Allen
A1 Richard Caswell
A1 Weijia Xie
A1 Xiao Xu
A1 Christopher Wragg
A1 Peter D Turnpenny
A1 Claire L S Turner
A1 Michael N Weedon
A1 Sian Ellard
YR 2014
UL http://jmg.bmj.com/content/51/4/264.abstract
AB Objective Split-hand/foot malformation type 1 is an autosomal dominant condition with reduced penetrance and variable expression. We report three individuals from two families with split-hand/split-foot malformation (SHFM) in whom next generation sequencing was performed to investigate the cause of their phenotype. Methods and results The first proband has a de novo balanced translocation t(2;7)(p25.1;q22) identified by karyotyping. Whole genome sequencing showed that the chromosome 7 breakpoint is situated within the SHFM1 locus on chromosome 7q21.3. This separates the DYNC1I1 exons recently identified as limb enhancers in mouse studies from their target genes, DLX5 and DLX6. In the second family, X-linked recessive inheritance was suspected and exome sequencing was performed to search for a mutation in the affected proband and his uncle. No coding mutation was found within the SHFM2 locus at Xq26 or elsewhere in the exome, but a 106 kb deletion within the SHFM1 locus was detected through copy number analysis. Genome sequencing of the deletion breakpoints showed that the DLX5 and DLX6 genes are disomic but the putative DYNC1I1 exon 15 and 17 enhancers are deleted. Conclusions Exome sequencing identified a 106 kb deletion that narrows the SHFM1 critical region from 0.9 to 0.1 Mb and confirms a key role of DYNC1I1 exonic enhancers in normal limb formation in humans.