Journal article
CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome
Human genetics, Vol.142(4), pp.523-530
04/2023
DOI: 10.1007/s00439-023-02538-0
PMCID: PMC10060348
PMID: 36929416
Abstract
Turner syndrome (TS) is a chromosomal disorder caused by complete or partial loss of the second sex chromosome and exhibits phenotypic heterogeneity, even after accounting for mosaicism and karyotypic variation. Congenital heart defects (CHD) are found in up to 45 percent of girls with TS and span a phenotypic continuum of obstructive left-sided lesions, with bicuspid aortic valve (BAV) being the most common. Several recent studies have demonstrated a genome-wide impact of X chromosome haploinsufficiency, including global hypomethylation and altered RNA expression. The presence of such broad changes to the TS epigenome and transcriptome led others to hypothesize that X chromosome haploinsufficiency sensitizes the TS genome, and several studies have demonstrated that a second genetic hit can modify disease susceptibility in TS. The objective of this study was to determine whether genetic variants in known heart developmental pathways act synergistically in this setting to increase the risk for CHD, specifically BAV, in TS. We analyzed 208 whole exomes from girls and women with TS and performed gene-based variant enrichment analysis and rare-variant association testing to identify variants associated with BAV in TS. Notably, rare variants in CRELD1 were significantly enriched in individuals with TS who had BAV compared to those with structurally normal hearts. CRELD1 is a protein that functions as a regulator of calcineurin/NFAT signaling, and rare variants in CRELD1 have been associated with both syndromic and non-syndromic CHD. This observation supports the hypothesis that genetic modifiers outside the X chromosome that lie in known heart development pathways may influence CHD risk in TS.
Details
- Title: Subtitle
- CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome
- Creators
- Catherina T Pinnaro - Stead Family Department of Pediatrics, University of Iowa, Iowa, IA, 52242, USAChloe B Beck - Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa, IA, 52242, USAHeather J Major - University of IowaBenjamin W Darbro - Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa, IA, 52242, USA. benjamin-darbro@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.142(4), pp.523-530
- DOI
- 10.1007/s00439-023-02538-0
- PMID
- 36929416
- PMCID
- PMC10060348
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Grant note
- K12 HD27748 / National Institute of Child Health and Human Development T32 DK112751 / NIDDK NIH HHS
- Language
- English
- Electronic publication date
- 03/16/2023
- Date published
- 04/2023
- Academic Unit
- Endocrinology and Diabetes; Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984378334502771
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