Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate

Huan Liu; Tamara Busch; Steven Eliason; Deepti Anand; Steven Bullard; Lord J J Gowans; Nichole Nidey; Aline Petrin; Eno-Abasi Augustine-Akpan; Irfan Saadi; Martine Dunnwald; Salil A Lachke; Ying Zhu; Adebowale Adeyemo; Brad Amendt; Tony Roscioli; Robert Cornell; Jeffrey Murray; Azeez Butali

doi:10.1002/bdra.23596

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Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate

Journal article

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Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate

Huan Liu, Tamara Busch, Steven Eliason, Deepti Anand, Steven Bullard, Lord J J Gowans, Nichole Nidey, Aline Petrin, Eno-Abasi Augustine-Akpan, Irfan Saadi, …

Birth defects research, Vol.109(1), pp.27-37

01/20/2017

DOI: 10.1002/bdra.23596

PMCID: PMC5388577

PMID: 28029220

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http://handle.unsw.edu.au/1959.4/unsworks_44265View

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Abstract

Recent advances in genomics methodologies, in particular the availability of next-generation sequencing approaches have made it possible to identify risk loci throughout the genome, in particular the exome. In the current study, we present findings from an exome study conducted in five affected individuals of a multiplex family with cleft palate only. The GEnome MINIng (GEMINI) pipeline was used to functionally annotate the single nucleotide polymorphisms, insertions and deletions. Filtering methods were applied to identify variants that are clinically relevant and present in affected individuals at minor allele frequencies (≤1%) in the 1000 Genomes Project single nucleotide polymorphism database, Exome Aggregation Consortium, and Exome Variant Server databases. The bioinformatics tool Systems Tool for Craniofacial Expression-Based Gene Discovery was used to prioritize cleft candidates in our list of variants, and Sanger sequencing was used to validate the presence of identified variants in affected and unaffected relatives. Our analyses approach narrowed the candidates down to the novel missense variant in ARHGAP29 (GenBank: NM_004815.3, NP_004806.3;c.1654T>C [p.Ser552Pro]. A functional assay in zebrafish embryos showed that the encoded protein lacks the activity possessed by its wild-type counterpart, and migration assays revealed that keratinocytes transfected with wild-type ARHGAP29 migrated faster than counterparts transfected with the p.Ser552Pro ARHGAP29 variant or empty vector (control). These findings reveal ARHGAP29 to be a regulatory protein essential for proper development of the face, identifies an amino acid that is key for this, and provides a potential new diagnostic tool.Birth Defects Research 109:27-37, 2017. © 2016 Wiley Periodicals, Inc.

Computational Biology

Gene Frequency - genetics

Genome-Wide Association Study

Humans

Risk Factors

Male

Cleft Palate - genetics

GTPase-Activating Proteins - metabolism

Zebrafish - embryology

Zebrafish - genetics

Whole Exome Sequencing

Exome

Cleft Lip - genetics

Animals

Pedigree

Alleles

Polymorphism, Single Nucleotide - genetics

Female

High-Throughput Nucleotide Sequencing

GTPase-Activating Proteins - genetics

Sequence Analysis, DNA - methods

Disease Models, Animal

Details

Title: Subtitle: Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate
Creators: Huan Liu - Department of Anatomy and Cell Biology, Iowa City, U.S.A
Tamara Busch - Department of Pediatrics, University of Iowa, Iowa City, U.S.A
Steven Eliason - Department of Anatomy and Cell Biology, Iowa City, U.S.A
Deepti Anand - Department of Biological Sciences, University of Delaware, Newark, DE, USA
Steven Bullard - Department of Internal Medicine, University of Iowa, Iowa City, U.S.A
Lord J J Gowans - Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, U.S.A
Nichole Nidey - Department of Pediatrics, University of Iowa, Iowa City, U.S.A
Aline Petrin - Department of Pediatrics, University of Iowa, Iowa City, U.S.A
Eno-Abasi Augustine-Akpan - Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, U.S.A
Irfan Saadi - Department of Anatomy and Cell Biology, University of Kansas Medical Center Kansas City, KS, USA
Martine Dunnwald - Department of Anatomy and Cell Biology, Iowa City, U.S.A
Salil A Lachke - Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, USA
Ying Zhu - Newcastle GOLD Service, Hunter Genetics, Waratah, NSW, Australia
Adebowale Adeyemo - Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, U.S.A
Brad Amendt - Dows Research Institute, University of Iowa, Iowa City, U.S.A
Tony Roscioli - The Kinghorn Centre for Clinical Genomics, Sydney, Australia
Robert Cornell - Department of Anatomy and Cell Biology, Iowa City, U.S.A
Jeffrey Murray - Department of Pediatrics, University of Iowa, Iowa City, U.S.A
Azeez Butali - Dows Research Institute, University of Iowa, Iowa City, U.S.A
Resource Type: Journal article
Publication Details: Birth defects research, Vol.109(1), pp.27-37
DOI: 10.1002/bdra.23596
PMID: 28029220
PMCID: PMC5388577
NLM abbreviation: Birth Defects Res
ISSN: 2472-1727
eISSN: 2472-1727
Publisher: Wiley; United States
Grant note: R01 DE023575 / NIDCR NIH HHS R01 DE026172 / NIDCR NIH HHS K99 DE022378 / NIDCR NIH HHS R01 AR067739 / NIAMS NIH HHS R00 DE022378 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS R37 DE008559 / NIDCR NIH HHS T90 DE023520 / NIDCR NIH HHS R03 DE024776 / NIDCR NIH HHS
Language: English
Date published: 01/20/2017
Academic Unit: Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Addiction Medicine; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025360502771

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