Journal article
Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428
Scientific reports, Vol.14(1), 8533
04/12/2024
DOI: 10.1038/s41598-024-58343-w
PMCID: PMC11014861
PMID: 38609424
Abstract
Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.
Details
- Title: Subtitle
- Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428
- Creators
- Anthony M Musolf - National Human Genome Research InstituteCristina M Justice - National Human Genome Research InstituteZeynep Erdogan-Yildirim - University of PittsburghSeppe Goovaerts - KU LeuvenAraceli Cuellar - University of California, DavisJohn R Shaffer - University of PittsburghMary L Marazita - University of PittsburghPeter Claes - KU LeuvenSeth M Weinberg - University of PittsburghJae Li - University of California, DavisCraig Senders - University of California, DavisMarike Zwienenberg - University of California, DavisEmil Simeonov - Medical University of SofiaRadka Kaneva - Medical University of SofiaTony Roscioli - UNSW SydneyLorena Di Pietro - Università Cattolica del Sacro CuoreMarta Barba - Università Cattolica del Sacro CuoreWanda Lattanzi - Università Cattolica del Sacro CuoreMichael L Cunningham - Seattle Children's HospitalPaul A Romitti - University of IowaSimeon A Boyadjiev - University of California, Davis
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.14(1), 8533
- DOI
- 10.1038/s41598-024-58343-w
- PMID
- 38609424
- PMCID
- PMC11014861
- eISSN
- 2045-2322
- Grant note
- Gabriela Miller KidsFirst program / NIH HHS U01 DD001223 / CDC HHS R01 DE027023 / NIH HHS R01 DE016886 / NIH HHS
- Language
- English
- Date published
- 04/12/2024
- Academic Unit
- Epidemiology; Biostatistics
- Record Identifier
- 9984584908002771
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