Duplication of <i>HEY2</i> in cardiac and neurologic development

Jordan, Valerie K.; Rosenfeld, Jill A.; Lalani, Seema R.; Scott, Daryl A.

doi:10.1002/ajmg.a.37086

Cited by 10 publications

(6 citation statements)

References 28 publications

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“…We believe that this represents a novel approach to identify the functional impact of evolutionarily relevant regulatory elements on brain structure. Intriguingly, a rare single gene duplication of HEY2 was identified in a child with cardiac and neurodevelopmental deficits, including disrupted speech development ( Jordan et al. 2015 ).…”

Section: Discussionmentioning

confidence: 99%

The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area

et al. 2020

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Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000–3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure.

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Section: Discussionmentioning

confidence: 99%

The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area

et al. 2020

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“…Deleterious mutations in other NOTCH pathway genes have been identified in patients with TOF including HEY2 (36) and JAG1 (37,38). For this reason, we compiled a list of NOTCH pathway genes using the MGI Gene Ontology Project and assessed the clustering of variants in these genes.…”

Section: Variants In Notch1 Are Most Commonly Present In Non-syndromimentioning

confidence: 99%

Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

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Miossec

Williams

et al. 2019

Circulation Research

148

198

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Rationale: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD) phenotype. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. Objective: We used whole exome sequencing (WES) to assess the prevalence of unique, deleterious variants in the largest cohort of non-syndromic TOF patients reported to date. Methods and Results: 829 TOF patients underwent WES. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database (gnomAD) and a scaled combined annotation-dependent depletion (CADD) score of ≥20. The clustering of variants in two genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5x10-8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbour unique, deleterious variants. 31 changes were observed in 37 probands (4.5%; 95% confidence interval [CI]:3.2-6.1%) and included seven loss-of-function variants 22 missense variants and two in-frame indels. Sanger-sequencing of the unaffected parents of seven cases identified five de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y and p.N1875S) were subjected to functional evaluation and two showed a reduction in Jagged1-induced NOTCH signalling. FLT4 variants were found in 2.4% (95% CI:1.6-3.8%) of TOF patients, with 21 patients harbouring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy Disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates including RYR1, ZFPM1, CAMTA2, DLX6 and PCM1. Conclusions: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.

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“…Hey2 mutations in both humans and mice cause a variety of cardiac morphogenetic defects, as well as a cardiomyocyte maturation defect. In humans, non-synonymous sequence changes in Hey2 correlate with atrioventricular septal defects and other cardiac defects 4 , 5 , and Hey2 duplication contributes to both congenital heart defects and neurodevelopmental defects 6 . Similarly, Hey2 knockout mice display defects including atrioventricular valvular defects, pulmonary stenosis, Tetralogy of Fallot, tricuspid atresia, and abnormal cardiac hemodynamics 7 – 9 , indicating that Hey2 is an essential regulator of cardiac morphogenesis and cardiac function.…”

Section: Introductionmentioning

confidence: 99%

Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification

Tian

et al. 2018

Sci Rep

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Hey2 gene mutations in both humans and mice have been associated with multiple cardiac defects. However, the currently reported localization of Hey2 in the ventricular compact zone cannot explain the wide variety of cardiac defects. Furthermore, it was reported that, in contrast to other organs, Notch doesn’t regulate Hey2 in the heart. To determine the expression pattern and the regulation of Hey2, we used novel methods including RNAscope and a Hey2CreERT2 knockin line to precisely determine the spatiotemporal expression pattern and level of Hey2 during cardiac development. We found that Hey2 is expressed in the endocardial cells of the atrioventricular canal and the outflow tract, as well as at the base of trabeculae, in addition to the reported expression in the ventricular compact myocardium. By disrupting several signaling pathways that regulate trabeculation and/or compaction, we found that, in contrast to previous reports, Notch signaling and Nrg1/ErbB2 regulate Hey2 expression level in myocardium and/or endocardium, but not its expression pattern: weak expression in trabecular myocardium and strong expression in compact myocardium. Instead, we found that FGF signaling regulates the expression pattern of Hey2 in the early myocardium, and regulates the expression level of Hey2 in a Notch1 dependent manner.

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Duplication of HEY2 in cardiac and neurologic development

Cited by 10 publications

References 28 publications

The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area

The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area

Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification

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