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Genetics January 1, 2018; 208 (1): 283-296.

Identification of Isthmin 1 as a Novel Clefting and Craniofacial Patterning Gene in Humans.

Lansdon LA , Darbro BW , Petrin AL , Hulstrand AM , Standley JM , Brouillette RB , Long A , Mansilla MA , Cornell RA , Murray JC , Houston DW , Manak JR .

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 hybridization has 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 palate only, 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 arch and is also in the same "synexpression group" 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 haploinsufficiency locus. Confirming its role in craniofacial development, knockdown or clustered randomly interspaced short palindromic repeats/Cas9-generated mutation of isthmin 1 in Xenopus laevis resulted in mild to severe craniofacial dysmorphologies, with several individuals presenting with median clefts. Moreover, knockdown of isthmin 1 produced decreased expression of LIM homeobox 8, 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 craniofacial patterning gene.

PubMed ID: 29162626
PMC ID: PMC5753863
Article link: Genetics
Grant support: [+]
Genes referenced: ism1 ctrl fgf8 lhx8 spry1 sptlc3 tasp1
GO Terms: face development [+]
Morpholinos: ism1 MO1 ism1 MO2

Disease Ontology terms: cleft palate [+]

Article Images: [+] show captions
Abecasis, 2012, Pubmed [+]

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