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Hum Mutat. 2019 Oct;40(10):1813-1825. doi: 10.1002/humu.23793. Epub 2019 Jun 18.

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans.

Author information

1
Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
2
Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington.
3
Department of Oral & Craniofacial Science, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri.
4
Lidral Orthodontics, Rockford, Michigan.
5
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio.
6
Department of Anatomy and Cell Biology and Anatomy, University of Iowa, Iowa City, Iowa.
7
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
8
New South Wales Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.
9
Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia.
10
Department of Orthodontics & the Iowa Institute for Oral Health Research, University of Iowa, Iowa City, Iowa.
11
Department of Biological Sciences, University of Delaware, Newark, Delaware.
12
Birth Defects Research Laboratory, University of Washington, Seattle, Washington.
13
Department of Pediatrics, University of Iowa, Iowa City, Iowa.
14
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.
15
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
16
Department of Genome Sciences, University of Washington, Seattle, Washington.
17
Centre for Clinical Genetics, Sydney Children's Hospital, New South Wales, Australia.
18
Centre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, Nijmegen, The Netherlands.
19
UVA Center for Advanced Medical Analytics, School of Medicine, University of Virginia, Charlottesville, Virginia.
20
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
21
Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
22
Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
23
Prince of Wales Clinical School, University of New South Wales, Randwick, New South Wales, Australia.
24
Neuroscience Research Australia (NeuRA), University of New South Wales, Sydney, New South Wales, Australia.

Abstract

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.

KEYWORDS:

GDF11; cleft lip; cleft palate; follistatin; vertebral hypersegmentation

PMID:
31215115
PMCID:
PMC6764866
[Available on 2020-10-01]
DOI:
10.1002/humu.23793

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