Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis

Cristina M. Justice; Anthony M. Musolf; Araceli Cuellar; Wanda Lattanzi; Emil Simeonov; Radka Kaneva; Justin Paschall; Michael Cunningham; Andrew O. M. Wilkie; Alexander F. Wilson; Paul A. Romitti; Simeon A. Boyadjiev

doi:10.3390/genes13050816

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Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis

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Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis

Cristina M. Justice, Anthony M. Musolf, Araceli Cuellar, Wanda Lattanzi, Emil Simeonov, Radka Kaneva, Justin Paschall, Michael Cunningham, Andrew O. M. Wilkie, Alexander F. Wilson, …

Genes, Vol.13(816), p.816

05/01/2022

DOI: 10.3390/genes13050816

PMCID: PMC9141801

PMID: 35627201

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Abstract

Craniosynostosis (CS) is a major birth defect in which one or more skull sutures fuse prematurely. We previously performed a genome-wide association study (GWAS) for sagittal non-syndromic CS (sNCS), identifying associations downstream from BMP2 on 20p12.3 and intronic to BBS9 on 7p14.3; analyses of imputed variants in DLG1 on 3q29 were also genome-wide significant. We followed this work with a GWAS for metopic non-syndromic NCS (mNCS), discovering a significant association intronic to BMP7 on 20q13.31. In the current study, we sequenced the associated regions on 3q29, 7p14.3, and 20p12.3, including two candidate genes (BMP2 and BMPER) near some of these regions in 83 sNCS child-parent trios, and sequenced regions on 7p14.3 and 20q13.2-q13.32 in 80 mNCS child-parent trios. These child-parent trios were selected from the original GWAS cohorts if the probands carried at least one copy of the top associated GWAS variant (rs1884302 C allele for sNCS; rs6127972 T allele for mNCS). Many of the variants sequenced in these targeted regions are strongly predicted to be within binding sites for transcription factors involved in craniofacial development or bone morphogenesis. Variants enriched in more than one trio and predicted to be damaging to gene function are prioritized for functional studies.

BMP7

craniosynostosis

metopic

nonsyndromic non-syndromic

sagittal

targeted sequencing

Details

Title: Subtitle: Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis
Creators: Cristina M. Justice - National Human Genome Research Institute
Anthony M. Musolf - National Human Genome Research Institute
Araceli Cuellar - University of California, Davis
Wanda Lattanzi - Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
Emil Simeonov - Medical University of Sofia
Radka Kaneva - Medical University of Sofia
Justin Paschall - National Human Genome Research Institute
Michael Cunningham - University of Washington
Andrew O. M. Wilkie - University of Oxford
Alexander F. Wilson - National Human Genome Research Institute
Paul A. Romitti - University of Iowa
Simeon A. Boyadjiev - University of California, Davis
Resource Type: Journal article
Publication Details: Genes, Vol.13(816), p.816
DOI: 10.3390/genes13050816
PMID: 35627201
PMCID: PMC9141801
NLM abbreviation: Genes (Basel)
eISSN: 2073-4425
Publisher: MDPI AG
Grant note: DOI: 10.13039/100000072, name: National Institute of Dental and Craniofacial Research, award: R01 DE016886, R01 DE018227; DOI: 10.13039/100000030, name: Centers for Disease Control and Prevention, award: U01 DD001223; DOI: 10.13039/100004440, name: Wellcome Trust, award: Investigator Award 102731; DOI: 10.13039/100000071, name: Eunice Kennedy Shriver National Institute of Child Health and Human Development, award: HHSN275201100001I, HHSN27500005; name: Center for Inherited Disease Research, award: HHSN268200782096C
Language: English
Date published: 05/01/2022
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9984259620102771

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