Details

Autor(en) / Beteiligte

• Lansdon, Lisa A
• Darbro, Benjamin W
• Petrin, Aline L
• Hulstrand, Alissa M
• Standley, Jennifer M
• Brouillette, Rachel B
• Long, Abby
• Mansilla, M Adela
• Cornell, Robert A
• Murray, Jeffrey C
• Houston, Douglas W
• Manak, J Robert

Titel

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

Ist Teil von

• Genetics (Austin), 2018-01, Vol.208 (1), p.283-296

Ort / Verlag

United States: Genetics Society of America

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 in one affected case, as well as a deletion in a second case that removes putative 3' regulatory information. 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 and and , all of which have been associated with clefting. CNVs affecting are exceedingly rare in control populations, and scores as a likely haploinsufficiency locus. Confirming its role in craniofacial development, knockdown or clustered randomly interspaced short palindromic repeats/Cas9-generated mutation of in resulted in mild to severe craniofacial dysmorphologies, with several individuals presenting with median clefts. Moreover, knockdown of produced decreased expression of , 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 as both a new human clefting locus as well as a key craniofacial patterning gene.