Publications by authors named "Sally L Dunwoodie"

100 Publications

Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction.

Cell Stem Cell 2021 Nov 5. Epub 2021 Nov 5.

Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia; St. Vincent's Clinical School, UNSW Sydney, NSW, Australia; School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, NSW, Australia. Electronic address:

We report that cardiac fibroblasts (CFs) and mesenchymal progenitors are more hypoxic than other cardiac interstitial populations, express more hypoxia-inducible factor 1α (HIF-1α), and exhibit increased glycolytic metabolism. CF-specific deletion of Hif-1a resulted in decreased HIF-1 target gene expression and increased mesenchymal progenitors in uninjured hearts and increased CF activation without proliferation following sham injury, as demonstrated using single-cell RNA sequencing (scRNA-seq). After myocardial infarction (MI), however, there was ∼50% increased CF proliferation and excessive scarring and contractile dysfunction, a scenario replicated in 3D engineered cardiac microtissues. CF proliferation was associated with higher reactive oxygen species (ROS) as occurred also in wild-type mice treated with the mitochondrial ROS generator MitoParaquat (MitoPQ). The mitochondrial-targeted antioxidant MitoTEMPO rescued Hif-1a mutant phenotypes. Thus, HIF-1α in CFs provides a critical braking mechanism against excessive post-ischemic CF activation and proliferation through regulation of mitochondrial ROS. CFs are potential cellular targets for designer antioxidant therapies in cardiovascular disease.
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http://dx.doi.org/10.1016/j.stem.2021.10.009DOI Listing
November 2021

Whole genome sequencing in transposition of the great arteries and associations with clinically relevant heart, brain and laterality genes.

Am Heart J 2021 Oct 17;244:1-13. Epub 2021 Oct 17.

Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia; Cincinnati Children's Hospital Medical Center, Heart Institute, Cardiothoracic Surgery, Cincinnati, OH. Electronic address:

Background: The most common cyanotic congenital heart disease (CHD) requiring management as a neonate is transposition of great arteries (TGA). Clinically, up to 50% of TGA patients develop some form of neurodevelopmental disability (NDD), thought to have a significant genetic component. A "ciliopathy" and links with laterality disorders have been proposed. This first report of whole genome sequencing in TGA, sought to identify clinically relevant variants contributing to heart, brain and laterality defects.

Methods: Initial whole genome sequencing analyses on 100 TGA patients focussed on established disease genes related to CHD (n = 107), NDD (n = 659) and heterotaxy (n = 74). Single variant as well as copy number variant analyses were conducted. Variant pathogenicity was assessed using the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.

Results: Fifty-five putatively damaging variants were identified in established disease genes associated with CHD, NDD and heterotaxy; however, no clinically relevant variants could be attributed to disease. Notably, case-control analyses identified significantly more predicted-damaging, silent and total variants in TGA cases than healthy controls in established CHD genes (P < .001), NDD genes (P < .001) as well as across the three gene panels (P < .001).

Conclusion: We present compelling evidence that the majority of TGA is not caused by monogenic rare variants and is most likely oligogenic and/or polygenic in nature, highlighting the complex genetic architecture and multifactorial influences on this CHD sub-type and its long-term sequelae. Assessment of variant burden in key heart, brain and/or laterality genes may be required to unravel the genetic contributions to TGA and related disabilities.
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http://dx.doi.org/10.1016/j.ahj.2021.10.185DOI Listing
October 2021

Simultaneous quantification of 26 NAD-related metabolites in plasma, blood, and liver tissue using UHPLC-MS/MS.

Anal Biochem 2021 11 12;633:114409. Epub 2021 Oct 12.

Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, 2052, Australia; Faculty of Science, University of New South Wales, Sydney, New South Wales, 2052, Australia. Electronic address:

Nicotinamide adenine dinucleotide (NAD) is a key metabolic intermediate found in all cells and involved in numerous cellular functions. Perturbances in the NAD metabolome are linked to various diseases such as diabetes and schizophrenia, and to congenital malformations and recurrent miscarriage. Mouse models are central to the investigation of these and other NAD-related conditions because mice can be readily genetically modified and treated with diets with altered concentrations of NAD precursors. Simultaneous quantification of as many metabolites of the NAD metabolome as possible is required to understand which pathways are affected in these disease conditions and what are the functional consequences. Here, we report the development of a fit-for-purpose method to simultaneously quantify 26 NAD-related metabolites and creatinine in mouse plasma, whole blood, and liver tissue using ultra-high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS). The included metabolites represent dietary precursors, intermediates, enzymatic cofactors, and excretion products. Sample preparation was optimized for each matrix and included 21 isotope-labeled internal standards. The method reached adequate precision and accuracy for the intended context of use of exploratory pathway-related biomarker discovery in mouse models. The method was tested by determining metabolite concentrations in mice fed a special diet with defined precursor content.
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http://dx.doi.org/10.1016/j.ab.2021.114409DOI Listing
November 2021

CITED2 inhibits STAT1-IRF1 signaling and atherogenesis.

FASEB J 2021 09;35(9):e21833

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Macrophages are the principal component of the innate immune system. They play very crucial and multifaceted roles in the pathogenesis of inflammatory vascular diseases. There is an increasing recognition that transcriptionally dynamic macrophages are the key players in the pathogenesis of inflammatory vascular diseases. In this context, the accumulation and aberrant activation of macrophages in the subendothelial layers govern atherosclerotic plaque development. Macrophage-mediated inflammation is an explicitly robust biological response that involves broad alterations in inflammatory gene expression. Thus, cell-intrinsic negative regulatory mechanisms must exist which can restrain inflammatory response in a spatiotemporal manner. In this study, we identified CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as one such cell-intrinsic negative regulator of inflammation. Our in vivo studies show that myeloid-CITED2-deficient mice on the Apoe background have larger atherosclerotic lesions on both control and high-fat/high-cholesterol diets. Our integrated transcriptomics and gene set enrichment analyses studies show that CITED2 deficiency elevates STAT1 and interferon regulatory factor 1 (IRF1) regulated pro-inflammatory gene expression in macrophages. At the molecular level, our studies identify that CITED2 deficiency elevates IFNγ-induced STAT1 transcriptional activity and STAT1 enrichment on IRF1 promoter in macrophages. More importantly, siRNA-mediated knockdown of IRF1 completely reversed elevated pro-inflammatory target gene expression in CITED2-deficient macrophages. Collectively, our study findings demonstrate that CITED2 restrains the STAT1-IRF1 signaling axis in macrophages and limits the development of atherosclerotic plaques.
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http://dx.doi.org/10.1096/fj.202100792RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607356PMC
September 2021

Precision Medicine in Cardiovascular Disease: Genetics and Impact on Phenotypes: JACC Focus Seminar 1/5.

J Am Coll Cardiol 2021 05;77(20):2517-2530

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, UNSW Sydney, Kensington, New South Wales, Australia; Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Our understanding of the genetic basis of cardiovascular diseases (CVDs) has evolved rapidly. This has resulted from a combination of dedicated research in well phenotyped CVD patients, the sequencing of the human genome, and the ready accessibility and decreasing cost of next-generation sequencing technologies. This increased knowledge of the genetic basis of CVDs has heralded the era of precision medicine. This encompasses many elements including improved diagnosis, family screening, assistance with reproductive decisions, targeted therapeutics guided by both phenotype and genotype, and providing important insights into risk stratification and prognosis. Furthermore, novel insights into genetic mechanisms, clinical rollout of polygenic risk scores for common CVDs, and the promise of genome editing approaches to effectively cure disease represent some of the exciting future endeavors that will change established clinical approaches. This Part 1 of a 5-part series focuses on the underpinnings and fundamental aspects of precision medicine.
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http://dx.doi.org/10.1016/j.jacc.2020.12.071DOI Listing
May 2021

A new era of genetic testing in congenital heart disease: A review.

Trends Cardiovasc Med 2021 May 5. Epub 2021 May 5.

Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. Electronic address:

Genetic and genomic testing in pediatric CHD is becoming increasingly routine, and can have important psychosocial, clinical and reproductive implications. In this paper we highlight important challenges and considerations when providing genetics consults and testing in pediatric CHD and illustrate the role of a dedicated CHD genetics clinic. Key lessons include that a) a genetic diagnosis can have clinical utility that justifies testing early in life, b) adequate genetic counselling is crucial to ensure families are supported, understand the range of possible results, and are prepared for new or unexpected health information, and c) further integration of the clinical genetics and cardiology workflows will be required to effectively manage the burgeoning information arising from genetic testing. Our experience demonstrates that a dedicated CHD genetics clinic is a valuable addition to a multidisciplinary team providing care to children with CHD.
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http://dx.doi.org/10.1016/j.tcm.2021.04.011DOI Listing
May 2021

New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder.

Hum Mutat 2021 Jul 16;42(7):862-876. Epub 2021 May 16.

Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme involved in over 400 cellular reactions. During embryogenesis, mammals synthesize NAD de novo from dietary l -tryptophan via the kynurenine pathway. Biallelic, inactivating variants in three genes encoding enzymes of this biosynthesis pathway (KYNU, HAAO, and NADSYN1) disrupt NAD synthesis and have been identified in patients with multiple malformations of the heart, kidney, vertebrae, and limbs; these patients have Congenital NAD Deficiency Disorder HAAO and four families with biallelic variants in KYNU. These patients present similarly with multiple malformations of the heart, kidney, vertebrae, and limbs, of variable severity. We show that each variant identified in these patients results in loss-of-function, revealed by a significant reduction in NAD levels via yeast genetic complementation assays. For the first time, missense mutations are identified as a cause of malformation and shown to disrupt enzyme function. These missense and frameshift variants cause moderate to severe NAD deficiency in yeast, analogous to insufficient synthesized NAD in patients. We hereby expand the genotypic and corresponding phenotypic spectrum of Congenital NAD Deficiency Disorder.
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http://dx.doi.org/10.1002/humu.24211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238843PMC
July 2021

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

Hum Mol Genet 2020 12;29(22):3662-3678

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G1X3, Canada.

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.
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http://dx.doi.org/10.1093/hmg/ddaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823106PMC
December 2020

Diseases of development: leveraging developmental biology to understand human disease.

Development 2020 11 12;147(21). Epub 2020 Nov 12.

University of Texas, Austin, TX 78712, USA

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http://dx.doi.org/10.1242/dev.197863DOI Listing
November 2020

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing.

Circ Genom Precis Med 2020 12 30;13(6):e003030. Epub 2020 Oct 30.

Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, United Kingdom (A.A.B., T.R.W., S.E.H., D.P., A.A.-H., A.W., D.K., N.J.S., D.A.).

Background: Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene sets that have a significant enrichment of rare variants.

Methods: We sequenced a cohort of 384 SCAD survivors from the United Kingdom, alongside 13 722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants and exome-wide and gene-set rare variant collapsing analyses.

Results: The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 genes (, , , , , , and ) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, was the highest-ranked gene, and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function.

Conclusions: By studying the largest sequenced cohort of SCAD survivors, we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders, and we highlight several new genes for future validation.
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http://dx.doi.org/10.1161/CIRCGEN.120.003030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748045PMC
December 2020

CITED2 limits pathogenic inflammatory gene programs in myeloid cells.

FASEB J 2020 09 22;34(9):12100-12113. Epub 2020 Jul 22.

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Monocyte-derived macrophages are the major innate immune cells that provide the first line of cellular defense against infections or injuries. These recruited macrophages at the site of inflammation are exposed to a broad range of cytokines that categorically incite a robust pro-inflammatory response. However, macrophage pro-inflammatory activation must be under exquisite control to avert unbridled inflammation. Thus, endogenous mechanisms must exist that rigorously preserve macrophage quiescence and yet, allow nimble pro-inflammatory macrophage response with precise spatiotemporal control. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a critical intrinsic negative regulator of inflammation, which broadly attenuates pro-inflammatory gene programs in macrophages. Our in vivo studies revealed that myeloid-CITED2 deficiency significantly heightened macrophages and neutrophils recruitment to the site of inflammation. Our integrated transcriptomics and gene set enrichment analysis (GSEA) studies uncovered that CITED2 deficiency broadly enhances NFκB targets, IFNγ/IFNα responses, and inflammatory response gene expression in macrophages. Using complementary gain- and loss-of-function studies, we observed that CITED2 overexpression attenuate and CITED2 deficiency elevate LPS-induced NFκB transcriptional activity and NFκB-p65 recruitment to target gene promoter in macrophages. More importantly, blockade of NFκB signaling completely reversed elevated pro-inflammatory gene expression in macrophages. Collectively, our findings show that CITED2 restrains NFκB activation and curtails broad pro-inflammatory gene programs in myeloid cells.
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http://dx.doi.org/10.1096/fj.202000864RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496281PMC
September 2020

A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies.

Front Pediatr 2020 23;8:310. Epub 2020 Jun 23.

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL ( = 211), ARM ( = 204), and EA/TEF ( = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in , and , genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.
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http://dx.doi.org/10.3389/fped.2020.00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324789PMC
June 2020

KIAA1217: A novel candidate gene associated with isolated and syndromic vertebral malformations.

Am J Med Genet A 2020 07 5;182(7):1664-1672. Epub 2020 May 5.

Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.

Vertebral malformations (VMs) are caused by alterations in somitogenesis and may occur in association with other congenital anomalies. The genetic etiology of most VMs remains unknown and their identification may facilitate the development of novel therapeutic and prevention strategies. Exome sequencing was performed on both the discovery cohort of nine unrelated probands from the USA with VMs and the replication cohort from China (Deciphering Disorders Involving Scoliosis & COmorbidities study). The discovery cohort was analyzed using the PhenoDB analysis tool. Heterozygous and homozygous, rare and functional variants were selected and evaluated for their ClinVar, HGMD, OMIM, GWAS, mouse model phenotypes, and other annotations to identify the best candidates. Genes with candidate variants in three or more probands were selected. The replication cohort was analyzed by another in-house developed pipeline. We identified rare heterozygous variants in KIAA1217 in four out of nine probands in the discovery cohort and in five out of 35 probands in the replication cohort. Collectively, we identified 11 KIAA1217 rare variants in 10 probands, three of which have not been described in gnomAD and one of which is a nonsense variant. We propose that genetic variations of KIAA1217 may contribute to the etiology of VMs.
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http://dx.doi.org/10.1002/ajmg.a.61607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128026PMC
July 2020

NAD deficiency due to environmental factors or gene-environment interactions causes congenital malformations and miscarriage in mice.

Proc Natl Acad Sci U S A 2020 02 3;117(7):3738-3747. Epub 2020 Feb 3.

Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia;

Causes for miscarriages and congenital malformations can be genetic, environmental, or a combination of both. Genetic variants, hypoxia, malnutrition, or other factors individually may not affect embryo development, however, they may do so collectively. Biallelic loss-of-function variants in or , two genes of the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are causative of congenital malformation and miscarriage in humans and mice. The variants affect normal embryonic development by disrupting the synthesis of NAD, a key factor in multiple biological processes, from its dietary precursor tryptophan, resulting in NAD deficiency. This study demonstrates that congenital malformations caused by NAD deficiency can occur independent of genetic disruption of NAD biosynthesis. C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy. When the dietary undersupply was combined with a maternal heterozygous variant in , which alone does not cause NAD deficiency or malformations, the incidence of embryo loss and malformations was significantly higher, suggesting a gene-environment interaction. Maternal and embryonic NAD levels were deficient. Mild hypoxia as an additional factor exacerbated the embryo outcome. Our data show that NAD deficiency as a cause of embryo loss and congenital malformation is not restricted to the rare cases of biallelic mutations in NAD synthesis pathway genes. Instead, monoallelic genetic variants and environmental factors can result in similar outcomes. The results expand our understanding of the causes of congenital malformations and the importance of sufficient NAD precursor consumption during pregnancy.
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http://dx.doi.org/10.1073/pnas.1916588117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035598PMC
February 2020

Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders.

Am J Hum Genet 2020 01 26;106(1):129-136. Epub 2019 Dec 26.

Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia; Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address:

Birth defects occur in up to 3% of all live births and are the leading cause of infant death. Here we present five individuals from four unrelated families, individuals who share similar phenotypes with disease-causal bi-allelic variants in NADSYN1, encoding NAD synthetase 1, the final enzyme of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway. Defects range from the isolated absence of both kidneys to multiple malformations of the vertebrae, heart, limbs, and kidney, and no affected individual survived for more than three months postnatally. NAD is an essential coenzyme for numerous cellular processes. Bi-allelic loss-of-function mutations in genes required for the de novo synthesis of NAD were previously identified in individuals with multiple congenital abnormalities affecting the heart, kidney, vertebrae, and limbs. Functional assessments of NADSYN1 missense variants, through a combination of yeast complementation and enzymatic assays, show impaired enzymatic activity and severely reduced NAD levels. Thus, NADSYN1 represents an additional gene required for NAD synthesis during embryogenesis, and NADSYN1 has bi-allelic missense variants that cause NAD deficiency-dependent malformations. Our findings expand the genotypic spectrum of congenital NAD deficiency disorders and further implicate mutation of additional genes involved in de novo NAD synthesis as potential causes of complex birth defects.
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http://dx.doi.org/10.1016/j.ajhg.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042491PMC
January 2020

Functional genomics and gene-environment interaction highlight the complexity of congenital heart disease caused by Notch pathway variants.

Hum Mol Genet 2020 03;29(4):566-579

Victor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.

Congenital heart disease (CHD) is the most common birth defect and brings with it significant mortality and morbidity. The application of exome and genome sequencing has greatly improved the rate of genetic diagnosis for CHD but the cause in the majority of cases remains uncertain. It is clear that genetics, as well as environmental influences, play roles in the aetiology of CHD. Here we address both these aspects of causation with respect to the Notch signalling pathway. In our CHD cohort, variants in core Notch pathway genes account for 20% of those that cause disease, a rate that did not increase with the inclusion of genes of the broader Notch pathway and its regulators. This is reinforced by case-control burden analysis where variants in Notch pathway genes are enriched in CHD patients. This enrichment is due to variation in NOTCH1. Functional analysis of some novel missense NOTCH1 and DLL4 variants in cultured cells demonstrate reduced signalling activity, allowing variant reclassification. Although loss-of-function variants in DLL4 are known to cause Adams-Oliver syndrome, this is the first report of a hypomorphic DLL4 allele as a cause of isolated CHD. Finally, we demonstrate a gene-environment interaction in mouse embryos between Notch1 heterozygosity and low oxygen- or anti-arrhythmic drug-induced gestational hypoxia, resulting in an increased incidence of heart defects. This implies that exposure to environmental insults such as hypoxia could explain variable expressivity and penetrance of observed CHD in families carrying Notch pathway variants.
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http://dx.doi.org/10.1093/hmg/ddz270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068028PMC
March 2020

VPOT: A Customizable Variant Prioritization Ordering Tool for Annotated Variants.

Genomics Proteomics Bioinformatics 2019 10 22;17(5):540-545. Epub 2019 Nov 22.

Victor Chang Cardiac Research Institute, Sydney 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney 2052, Australia. Electronic address:

Next-generation sequencing (NGS) technologies generate thousands to millions of genetic variants per sample. Identification of potential disease-causal variants is labor intensive as it relies on filtering using various annotation metrics and consideration of multiple pathogenicity prediction scores. We have developed VPOT (variant prioritization ordering tool), a python-based command line tool that allows researchers to create a single fully customizable pathogenicity ranking score from any number of annotation values, each with a user-defined weighting. The use of VPOT can be informative when analyzing entire cohorts, as variants in a cohort can be prioritized. VPOT also provides additional functions to allow variant filtering based on a candidate gene list or by affected status in a family pedigree. VPOT outperforms similar tools in terms of efficacy, flexibility, scalability, and computational performance. VPOT is freely available for public use at GitHub (https://github.com/VCCRI/VPOT/). Documentation for installation along with a user tutorial, a default parameter file, and test data are provided.
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http://dx.doi.org/10.1016/j.gpb.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056850PMC
October 2019

Functional characterization of a novel PBX1 de novo missense variant identified in a patient with syndromic congenital heart disease.

Hum Mol Genet 2020 05;29(7):1068-1082

Victor Chang Cardiac Research Institute, Department of Embryology, New South Wales, 2010 Sydney, Australia.

Pre-B cell leukemia factor 1 (PBX1) is an essential developmental transcription factor, mutations in which have recently been associated with CAKUTHED syndrome, characterized by multiple congenital defects including congenital heart disease (CHD). During analysis of a whole-exome-sequenced cohort of heterogeneous CHD patients, we identified a de novo missense variant, PBX1:c.551G>C p.R184P, in a patient with tetralogy of Fallot with absent pulmonary valve and extra-cardiac phenotypes. Functional analysis of this variant by creating a CRISPR-Cas9 gene-edited mouse model revealed multiple congenital anomalies. Congenital heart defects (persistent truncus arteriosus and ventricular septal defect), hypoplastic lungs, hypoplastic/ectopic kidneys, aplastic adrenal glands and spleen, as well as atretic trachea and palate defects were observed in the homozygous mutant embryos at multiple stages of development. We also observed developmental anomalies in a proportion of heterozygous embryos, suggestive of a dominant mode of inheritance. Analysis of gene expression and protein levels revealed that although Pbx1 transcripts are higher in homozygotes, amounts of PBX1 protein are significantly decreased. Here, we have presented the first functional model of a missense PBX1 variant and provided strong evidence that p.R184P is disease-causal. Our findings also expand the phenotypic spectrum associated with pathogenic PBX1 variants in both humans and mice.
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http://dx.doi.org/10.1093/hmg/ddz231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206850PMC
May 2020

'Big issues' in neurodevelopment for children and adults with congenital heart disease.

Open Heart 2019;6(2):e000998. Epub 2019 Jul 3.

Heart Centre for Children, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

It is established that neurodevelopmental disability (NDD) is common in neonates undergoing complex surgery for congenital heart disease (CHD); however, the trajectory of disability over the lifetime of individuals with CHD is unknown. Several 'big issues' remain undetermined and further research is needed in order to optimise patient care and service delivery, to assess the efficacy of intervention strategies and to promote best outcomes in individuals of all ages with CHD. This review article discusses 'gaps' in our knowledge of NDD in CHD and proposes future directions.
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http://dx.doi.org/10.1136/openhrt-2018-000998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615801PMC
February 2021

Spliceogen: an integrative, scalable tool for the discovery of splice-altering variants.

Bioinformatics 2019 11;35(21):4405-4407

Victor Chang Cardiac Research Institute, Sydney, Australia.

Motivation: In silico prediction tools are essential for identifying variants which create or disrupt cis-splicing motifs. However, there are limited options for genome-scale discovery of splice-altering variants.

Results: We have developed Spliceogen, a highly scalable pipeline integrating predictions from some of the individually best performing models for splice motif prediction: MaxEntScan, GeneSplicer, ESRseq and Branchpointer.

Availability And Implementation: Spliceogen is available as a command line tool which accepts VCF/BED inputs and handles both single nucleotide variants (SNVs) and indels (https://github.com/VCCRI/Spliceogen). SNV databases with prediction scores are also available, covering all possible SNVs at all genomic positions within all Gencode-annotated multi-exon transcripts.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz263DOI Listing
November 2019

The pro-death role of Cited2 in stroke is regulated by E2F1/4 transcription factors.

J Biol Chem 2019 05 9;294(21):8617-8629. Epub 2019 Apr 9.

University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Hotchkiss Brain Institute, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada. Electronic address:

We previously reported that the cell cycle-related cyclin-dependent kinase 4-retinoblastoma (RB) transcriptional corepressor pathway is essential for stroke-induced cell death both and However, how this signaling pathway induces cell death is unclear. Previously, we found that the cyclin-dependent kinase 4 pathway activates the pro-apoptotic transcriptional co-regulator Cited2 after DNA damage. In the present study, we report that Cited2 protein expression is also dramatically increased following stroke/ischemic insult. Critically, utilizing conditional knockout mice, we show that Cited2 is required for neuronal cell death, both in culture and in mice after ischemic insult. Importantly, determining the mechanism by which Cited2 levels are regulated, we found that E2F transcription factor (E2F) family members participate in Cited2 regulation. First, E2F1 expression induced transcription, and E2F1 deficiency reduced expression. Moreover, determining the potential E2F-binding regions on the gene regulatory sequence by ChIP analysis, we provide evidence that E2F1/4 proteins bind to this DNA region. A luciferase reporter assay to probe the functional outcomes of this interaction revealed that E2F1 activates and E2F4 inhibits transcription. Moreover, we identified the functional binding motif for E2F1 in the gene promoter by demonstrating that mutation of this site dramatically reduces E2F1-mediated transcription. Finally, E2F1 and E2F4 regulated expression in neurons after stroke-related insults. Taken together, these results indicate that the E2F- regulatory pathway is critically involved in stroke injury.
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http://dx.doi.org/10.1074/jbc.RA119.007941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544850PMC
May 2019

A Diagnosis for All Rare Genetic Diseases: The Horizon and the Next Frontiers.

Cell 2019 03;177(1):32-37

Faculty of Health and Medical Sciences, University of Western Australia Medical School, Perth, WA, Australia; Western Australian Register of Developmental Anomalies, Genetic Services of Western Australia, Perth, WA, Australia; Office of Population Health Genomics, Western Australian Department of Health, Perth, WA, Australia.

The introduction of exome sequencing in the clinic has sparked tremendous optimism for the future of rare disease diagnosis, and there is exciting opportunity to further leverage these advances. To provide diagnostic clarity to all of these patients, however, there is a critical need for the field to develop and implement strategies to understand the mechanisms underlying all rare diseases and translate these to clinical care.
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http://dx.doi.org/10.1016/j.cell.2019.02.040DOI Listing
March 2019

Gene-environment interaction impacts on heart development and embryo survival.

Development 2019 02 20;146(4). Epub 2019 Feb 20.

Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia

Congenital heart disease (CHD) is the most common type of birth defect. In recent years, research has focussed on identifying the genetic causes of CHD. However, only a minority of CHD cases can be attributed to single gene mutations. In addition, studies have identified different environmental stressors that promote CHD, but the additive effect of genetic susceptibility and environmental factors is poorly understood. In this context, we have investigated the effects of short-term gestational hypoxia on mouse embryos genetically predisposed to heart defects. Exposure of mouse embryos heterozygous for or to hypoxia increased the incidence and severity of heart defects while embryos died within 2 days of hypoxic exposure. We identified the molecular consequences of the interaction between and short-term gestational hypoxia, which suggest that reduced expression and a prolonged hypoxia-inducible factor 1α response together precipitate embryo death. Our study provides insight into the causes of embryo loss and variable penetrance of monogenic CHD, and raises the possibility that cases of foetal death and CHD in humans could be caused by similar gene-environment interactions.
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http://dx.doi.org/10.1242/dev.172957DOI Listing
February 2019

Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.

J Am Coll Cardiol 2019 01;73(1):58-66

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia.

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.

Objectives: This study sought to test the association between the rs9349379 genotype and SCAD.

Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.

Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.

Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
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http://dx.doi.org/10.1016/j.jacc.2018.09.085DOI Listing
January 2019

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

Circ Res 2019 02;124(4):553-563

Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford (W.G.N.); and Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK.

Rationale: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date.

Objective: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date.

Methods And Results: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 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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http://dx.doi.org/10.1161/CIRCRESAHA.118.313250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377791PMC
February 2019

Identification of clinically actionable variants from genome sequencing of families with congenital heart disease.

Genet Med 2019 05 8;21(5):1111-1120. Epub 2018 Oct 8.

Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia.

Purpose: Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients.

Methods: Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband-parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines.

Results: Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families.

Conclusions: Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.
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http://dx.doi.org/10.1038/s41436-018-0296-xDOI Listing
May 2019

Genetic burden and associations with adverse neurodevelopment in neonates with congenital heart disease.

Am Heart J 2018 07 5;201:33-39. Epub 2018 Apr 5.

Kids Heart Research, The Children's Hospital at Westmead, Sydney, Australia; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia. Electronic address:

Background: Up to 20% of children with congenital heart disease (CHD) undergoing cardiac surgery develop neurodevelopmental disabilities (NDD), with some studies reporting persistent impairment. Recent large-scale studies have demonstrated shared genetic mechanisms contributing to CHD and NDD. In this study, a targeted approach was applied to assess direct clinical applicability of this information.

Methods: A gene panel comprising 148 known CHD and/or NDD genes was used to sequence 15 patients with CHD + NDD, 15 patients with CHD, and 15 healthy controls. The number and types of variants between the 3 groups were compared using Poisson log-linear regression, and the SNP-set (Sequence) Kernel Association Test-Optimized was used to conduct single-gene and gene-pathway burden analyses.

Results: A significant increase in rare (minor allele frequency < 0.01) and novel variants was identified between the CHD + NDD cohort and controls, P < .001 and P = .001, respectively. There was also a significant increase in rare variants in the CHD cohort compared with controls (P = .04). Rare variant burden analyses implicated pathways associated with "neurotransmitters," "axon guidance," and those incorporating "RASopathy" genes in the development of NDD in CHD patients.

Conclusions: These findings suggest that an increase in novel and rare variants in known CHD and/or NDD genes is associated with the development of NDD in patients with CHD. Furthermore, burden analyses point toward rare variant burden specifically in pathways related to brain development and function as contributors to NDD. Although promising variants and pathways were identified, further research, utilizing whole-genome approaches, is required prior to demonstrating clinical utility in this patient group.
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http://dx.doi.org/10.1016/j.ahj.2018.03.021DOI Listing
July 2018

A Screening Approach to Identify Clinically Actionable Variants Causing Congenital Heart Disease in Exome Data.

Circ Genom Precis Med 2018 03;11(3):e001978

From the Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia (J.O.S., H.C., D.T.H., E.I., E.G., D.B.S., J.W.K.H., R.M.G., G.C., S.L.D.); Faculty of Science (J.O.S., S.L.D.) and Faculty of Medicine (H.C., D.T.H., E.I., E.G., D.B.S., J.W.K.H., R.M.G., G.C., S.L.D.), University of New South Wales, Sydney, New South Wales, Australia, Sydney, New South Wales, Australia; Children's Hospital at Westmead, Heart Centre for Children (G.M.B., G.F.S., D.S.W.), Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, New South Wales, Australia (G.M.B., G.F.S., D.S.W.); Genetic Services of Western Australia, Perth (K.H., N.P.); Sydney Children's Hospitals Network, New South Wales, Australia (G.F.S.); Institute of Health and Biomedical Innovation, Queensland University of Technology (P.L., E.L.D.); Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia (E.L.D.); University of Queensland, Brisbane (E.L.D.); and School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia (N.P.).

Background: Congenital heart disease (CHD)-structural abnormalities of the heart that arise during embryonic development-is the most common inborn malformation, affecting ≤1% of the population. However, currently, only a minority of cases can be explained by genetic abnormalities. The goal of this study was to identify disease-causal genetic variants in 30 families affected by CHD.

Methods: Whole-exome sequencing was performed with the DNA of multiple family members. We utilized a 2-tiered whole-exome variant screening and interpretation procedure. First, we manually curated a high-confidence list of 90 genes known to cause CHD in humans, identified predicted damaging variants in genes on this list, and rated their pathogenicity using American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.

Results: In 3 families (10%), we found pathogenic variants in known CHD genes , , and , explaining the cardiac lesions. Second, exomes were comprehensively analyzed to identify additional predicted damaging variants that segregate with disease in CHD candidate genes. In 10 additional families (33%), likely disease-causal variants were uncovered in , , , , , , , , , , and .

Conclusions: The pathogenesis of CHD could be explained using our high-confidence CHD gene list for variant filtering in a subset of cases. Furthermore, our unbiased screening procedure of family exomes implicates additional genes and variants in the pathogenesis of CHD, which suggest themselves for functional validation. This 2-tiered approach provides a means of (1) identifying clinically actionable variants and (2) identifying additional disease-causal genes, both of which are essential for improving the molecular diagnosis of CHD.
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http://dx.doi.org/10.1161/CIRCGEN.117.001978DOI Listing
March 2018

Four-Generation Family With Ebstein Anomaly Highlights Future Challenges in Congenital Heart Disease Genetics.

Circ Cardiovasc Genet 2017 12;10(6)

From the Heart Centre for Children, Children's Hospital at Westmead (D.S.W.), Sydney Children's Hospitals Network (D.S.W., E.P.K.), Faculty of Medicine (D.S.W.), and Centre for Clinical Genetics, Sydney Children's Hospital (E.P.K.), University of Sydney, Randwick, NSW, Australia; Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia (D.S.W., S.L.D.); Faculties of Medicine and Science (S.L.D.) and School of Women's and Children's Health (E.P.K.), University of New South Wales, Randwick, Australia; and NSW Health Pathology Randwick Genetics Laboratory, Australia (E.P.K.).

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http://dx.doi.org/10.1161/CIRCGENETICS.117.001967DOI Listing
December 2017

Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16-18, 2017, Dallas, Texas.

Am J Med Genet A 2018 01 21;176(1):253-256. Epub 2017 Nov 21.

Texas Scottish Rite Hospital for Children, Dallas, Texas.

Scoliosis represents the most common musculoskeletal disorder in children and affects approximately 3% of the world population. Scoliosis is separated into two major phenotypic classifications: congenital and idiopathic. Idiopathic scoliosis is defined as a curvature of the spine of 10° or greater visualized on plane radiograph and does not have associated vertebral malformations (VM). "Congenital" scoliosis (CS) due to malformations in vertebrae is frequently associated with other birth defects. Recently, significant advances have been made in understanding the genetic basis of both conditions. There is evidence that both conditions are etiologically related. A 2-day conference entitled "Genomic Approaches to Understanding and Treating Scoliosis" was held at Scottish Rite Hospital for Children in Dallas, Texas, to synergize research in this field. This first combined, multidisciplinary conference featured international scoliosis researchers in basic and clinical sciences. A major outcome of the conference advancing scoliosis research was the proposal and subsequent vote in favor of merging the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) and International Consortium for Scoliosis Genetics (ICSG) into a single entity called International Consortium for Spinal Genetics, Development, and Disease (ICSGDD). The ICSGDD is proposed to meet annually as a forum to synergize multidisciplinary spine deformity research.
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http://dx.doi.org/10.1002/ajmg.a.38550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525596PMC
January 2018
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