@article {674,
	title = {Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans.},
	journal = {Hum Mutat},
	volume = {40},
	year = {2019},
	month = {2019 10},
	pages = {1813-1825},
	abstract = {<p>Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70\% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30\%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.</p>},
	issn = {1098-1004},
	doi = {10.1002/humu.23793},
	author = {Cox, Timothy C and Lidral, Andrew C and McCoy, Jason C and Liu, Huan and Cox, Liza L and Zhu, Ying and Anderson, Ryan D and Moreno Uribe, Lina M and Anand, Deepti and Deng, Mei and Richter, Chika T and Nidey, Nichole L and Standley, Jennifer M and Blue, Elizabeth E and Chong, Jessica X and Smith, Joshua D and Kirk, Edwin P and Venselaar, Hanka and Krahn, Katy N and van Bokhoven, Hans and Zhou, Huiqing and Cornell, Robert A and Glass, Ian A and Bamshad, Michael J and Nickerson, Deborah A and Murray, Jeffrey C and Lachke, Salil A and Thompson, Thomas B and Buckley, Michael F and Roscioli, Tony}
}
@article {474,
	title = {Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.},
	journal = {Am J Hum Genet},
	volume = {102},
	year = {2018},
	month = {2018 06 07},
	pages = {1143-1157},
	abstract = {<p>Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14\% of multi-affected families and 2\% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.</p>},
	keywords = {Alleles, Amino Acid Sequence, Animals, Biotinylation, Cadherins, Catenins, Cleft Lip, Cleft Palate, Epithelium, Female, Gene Deletion, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, Male, Mice, Mutation, Palate, Pedigree, Syndrome, Whole Exome Sequencing},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2018.04.009},
	author = {Cox, Liza L and Cox, Timothy C and Moreno Uribe, Lina M and Zhu, Ying and Richter, Chika T and Nidey, Nichole and Standley, Jennifer M and Deng, Mei and Blue, Elizabeth and Chong, Jessica X and Yang, Yueqin and Carstens, Russ P and Anand, Deepti and Lachke, Salil A and Smith, Joshua D and Dorschner, Michael O and Bedell, Bruce and Kirk, Edwin and Hing, Anne V and Venselaar, Hanka and Valencia-Ramirez, Luz C and Bamshad, Michael J and Glass, Ian A and Cooper, Jonathan A and Haan, Eric and Nickerson, Deborah A and van Bokhoven, Hans and Zhou, Huiqing and Krahn, Katy N and Buckley, Michael F and Murray, Jeffrey C and Lidral, Andrew C and Roscioli, Tony}
}
