Identification of Isthmin 1 as a Novel Clefting and Craniofacial Patterning Gene in Humans
2018
Orofacial clefts are one of the most common birth defects, affecting 1–2 per 1000 births, and have a complex etiology. High-resolution array-based
comparative genomic hybridizationhas increased the ability to detect copy number variants (CNVs) that can be causative for complex diseases such as cleft lip and/or palate. Utilizing this technique on 97 nonsyndromic cleft lip and palate cases and 43 cases with
cleft palateonly, we identified a heterozygous deletion of Isthmin 1 in one affected case, as well as a deletion in a second case that removes putative 3′ regulatory information. Isthmin 1 is a strong candidate for clefting, as it is expressed in orofacial structures derived from the
first branchial archand is also in the same “
synexpressiongroup” as fibroblast growth factor 8 and sprouty RTK signaling antagonist 1a and 2 , all of which have been associated with clefting. CNVs affecting Isthmin 1 are exceedingly rare in control populations, and Isthmin 1 scores as a likely
haploinsufficiencylocus. Confirming its role in
craniofacialdevelopment, knockdown or clustered randomly interspaced short
palindromicrepeats/
Cas9-generated mutation of isthmin 1 in Xenopus laevis resulted in mild to severe
craniofacialdysmorphologies, with several individuals presenting with median clefts. Moreover, knockdown of isthmin 1 produced decreased expression of LIM
homeobox8 , itself a gene associated with clefting, in regions of the face that pattern the maxilla. Our study demonstrates a successful pipeline from CNV identification of a candidate gene to functional validation in a vertebrate model system, and reveals Isthmin 1 as both a new human clefting locus as well as a key
craniofacialpatterning gene.
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