Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for DYNC1I1 exonic enhancers of DLX5/6 expression in humans.
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.
['Lango Allen|Hana|H|', 'Caswell|Richard|R|', 'Xie|Weijia|W|', 'Xu|Xiao|X|', 'Wragg|Christopher|C|', 'Turnpenny|Peter D|PD|', 'Turner|Claire L S|CL|', 'Weedon|Michael N|MN|', 'Ellard|Sian|S|']
D000818:Animals D002869:Chromosome Aberrations D056445:Cytoplasmic Dyneins D004742:Enhancer Elements, Genetic D005091:Exons D005190:Family D005260:Female D005786:Gene Expression Regulation D015321:Gene Rearrangement D056426:Genetic Loci D059014:High-Throughput Nucleotide Sequencing D018398:Homeodomain Proteins D006801:Humans D017880:Limb Deformities, Congenital D008297:Male D051379:Mice D009154:Mutation D019683:Penetrance D014157:Transcription Factors
Chromosomal Clinical Genetics Copy-Number Genetics