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 that can be causative for complex diseases such as cleft lip and/or palate. Utilizing this technique on 97 non-syndromic 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 which 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. Copy number variants 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 CRISPR/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 copy number variant 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.
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 January 2018.
All research outputs
#17,537,019
of 27,788,586 outputs
Outputs from Genetics
#6,131
of 7,829 outputs
Outputs of similar age
#259,911
of 457,925 outputs
Outputs of similar age from Genetics
#49
of 69 outputs
Altmetric has tracked 27,788,586 research outputs across all sources so far. This one is in the 36th percentile – i.e., 36% of other outputs scored the same or lower than it.
So far Altmetric has tracked 7,829 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.4. This one is in the 20th percentile – i.e., 20% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 457,925 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 42nd percentile – i.e., 42% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 69 others from the same source and published within six weeks on either side of this one. This one is in the 27th percentile – i.e., 27% of its contemporaries scored the same or lower than it.
