Impact of MYH6 Variants in Hypoplastic Left Heart Syndrome

Published on Dec 1, 2016in Physiological Genomics2.749
· DOI :10.1152/PHYSIOLGENOMICS.00091.2016
Aoy Tomita-Mitchell19
Estimated H-index: 19
(MCW: Medical College of Wisconsin),
Karl Stamm8
Estimated H-index: 8
(Marquette University)
+ 11 AuthorsMichael E. Mitchell17
Estimated H-index: 17
(MCW: Medical College of Wisconsin)
Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P < 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P < 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue reveale...
📖 Papers frequently viewed together
3,862 Citations
346 Citations
70 Citations
#1Jeanne L. Theis (Mayo Clinic)H-Index: 11
#2Michael T. Zimmermann (Mayo Clinic)H-Index: 23
Last. Timothy M. Olson (Mayo Clinic)H-Index: 31
view all 8 authors...
Background— The molecular underpinnings of hypoplastic left heart are poorly understood. Staged surgical palliation has dramatically improved survival, yet eventual failure of the systemic right ventricle necessitates cardiac transplantation in a subset of patients. We sought to identify genetic determinants of hypoplastic left heart with latent right ventricular dysfunction in individuals with a Fontan circulation. Methods and Results— Evaluation of cardiac structure and function by echocardiog...
44 CitationsSource
#1Min-Su Kim (MCW: Medical College of Wisconsin)H-Index: 6
#2Audrey Horst (MCW: Medical College of Wisconsin)H-Index: 3
Last. John Lough (MCW: Medical College of Wisconsin)H-Index: 31
view all 9 authors...
The use of human pluripotent cell progeny for cardiac disease modeling, drug testing and therapeutics requires the ability to efficiently induce pluripotent cells into the cardiomyogenic lineage. Although direct activation of the Activin-A and/or Bmp pathways with growth factors yields context-dependent success, recent studies have shown that induction of Wnt signaling using low molecular weight molecules such as CHIR, which in turn induces the Activin-A and Bmp pathways, is widely effective. To...
21 CitationsSource
#1Stamatia Kalogirou (Academy of Athens)H-Index: 2
#2Nikos Malissovas (Academy of Athens)H-Index: 3
Last. Dimitris Beis (Academy of Athens)H-Index: 17
view all 6 authors...
Aims Valvular heart disease is responsible for considerable morbidity and mortality. Cardiac valves develop as the heart contracts, and they function throughout the lifetime of the organism to prevent retrograde blood flow. Their precise morphogenesis is crucial for cardiac function. Zebrafish is an ideal model to investigate cardiac valve development as it allows these studies to be carried out in vivo through non-invasive imaging. Accumulating evidence suggests a role for contractility and int...
54 CitationsSource
#1Daniel G. MacArthur (Broad Institute)H-Index: 80
#2Teri A. Manolio (NIH: National Institutes of Health)H-Index: 117
Last. Chris GunterH-Index: 14
view all 27 authors...
The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges ...
952 CitationsSource
#1Dorothy Warburton (Columbia University)H-Index: 67
#2Michael RonemusH-Index: 16
Last. Michael WiglerH-Index: 120
view all 17 authors...
Congenital heart disease (CHD) is the most common congenital malformation, with evidence of a strong genetic component. We analyzed data from 223 consecutively ascertained families, each consisting of at least one child affected by a conotruncal defect (CNT) or hypoplastic left heart disease (HLHS) and both parents. The NimbleGen HD2-2.1 comparative genomic hybridization platform was used to identify de novo and rare inherited copy number variants (CNVs). Excluding 10 cases with 22q11.2 DiGeorge...
96 CitationsSource
#1Marcin WolnyH-Index: 10
#2Melanie ColegraveH-Index: 3
Last. Michelle PeckhamH-Index: 33
view all 6 authors...
It is unclear why mutations in the filament-forming tail of myosin heavy chain (MHC) cause hypertrophic or dilated cardiomyopathy as these mutations should not directly affect contraction. To investigate this, we first investigated the impact of five hypertrophic cardiomyopathy-causing (N1327K, E1356K, R1382W, E1555K, and R1768K) and one dilated cardiomyopathy-causing (R1500W) tail mutations on their ability to incorporate into muscle sarcomeres in vivo. We used adenoviral delivery to express fu...
22 CitationsSource
#1Motoshi Kaya (UTokyo: University of Tokyo)H-Index: 10
#2Hideo Higuchi (UTokyo: University of Tokyo)H-Index: 47
In muscles, the arrays of skeletal myosin molecules interact with actin filaments and continuously generate force at various contraction speeds. Therefore, it is crucial for myosin molecules to generate force collectively and minimize the interference between individual myosin molecules. Knowledge of the elasticity of myosin molecules is crucial for understanding the molecular mechanisms of muscle contractions because elasticity directly affects the working and drag (resistance) force generation...
26 CitationsSource
#1Aoy Tomita-Mitchell (MCW: Medical College of Wisconsin)H-Index: 19
#2Donna K. MahnkeH-Index: 8
Last. Michael E. MitchellH-Index: 51
view all 14 authors...
The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach...
75 CitationsSource
#1Cammon B. Arrington (UofU: University of Utah)H-Index: 16
#2Steven B. BleylH-Index: 22
Last. Neil E. BowlesH-Index: 50
view all 10 authors...
Background— A number of single gene defects have been identified in patients with isolated or nonsyndromic congenital heart defects (CHDs). However, due to significant genetic heterogeneity, candidate gene approaches have had limited success in finding high-risk alleles in most cases. The purpose of this study was to use exome sequencing to identify high-risk gene variants in a family with highly penetrant pleiotropic CHD. Methods and Results— DNA samples from 2 members of a family with diverse ...
54 CitationsSource
#1Maximilian G. Posch (Charité)H-Index: 20
Last. Cemil Özcelik (Charité)H-Index: 26
view all 16 authors...
Secundum-type atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD) and are associated with a familial risk. Mutations in transcription factors represent a genetic source for ASDII. Yet, little is known about the role of mutations in sarcomeric genes in ASDII etiology. To assess the role of sarcomeric genes in patients with inherited ASDII, we analyzed 13 sarcomeric genes (MYH7, MYBPC3, TNNT2, TCAP, TNNI3, MYH6, TPM1, MYL2, CSRP3, ACTC1, MYL3, TNNC1, a...
61 CitationsSource
Cited By40
#1Shufang Huang (Peking Union Medical College)H-Index: 1
#2Yueheng Wu (Peking Union Medical College)H-Index: 1
Last. Yu Xia (Guangzhou University of Chinese Medicine)
view all 9 authors...
Abstract null null Objective null Atrial septal defect, secundum (ASD Ⅱ, OMIM: null 603642 ) is the second common congenital heart defect (CHD) in China. However, the genetic etiology of familial ASD II remains elusive. null null null Methods and results null Using whole-exome sequencing (WES) and Sanger sequencing, we identified a novel myosin heavy chain 6 (MYH6) gene insertion variation, NM_002471.3: c.5465_5470dup (Arg1822_Glu1823dup), in a large Chinese Han family with ASD II. The variant A...
#1Anthony T Bejjani (Cincinnati Children's Hospital Medical Center)
#2Neil Wary (Cincinnati Children's Hospital Medical Center)
Last. Mingxia Gu (Cincinnati Children's Hospital Medical Center)H-Index: 18
view all 3 authors...
Introduction null Hypoplastic left heart syndrome (HLHS) is a severe developmental defect characterized by the underdevelopment of the left ventricle along with aortic and valvular defects. Multiple palliative surgeries are required for survival. Emerging studies have identified potential mechanisms for the disease onset, including genetic and hemodynamic causes. Genetic variants associated with HLHS include transcription factors, chromatin remodelers, structural proteins, and signaling proteins...
Objective: To study the associations of a single nucleotide polymorphisms (SNP) of the myosin heavy chain 6 (MYH6) gene with the risk of atrial fibrillation (AF) and warfarin anticoagulation therap...
#1Iwona Strzelecka (Medical University of Łódź)H-Index: 3
#2M Biedrzycka (Medical University of Łódź)
Last. Maria Respondek-Liberska (Memorial Hospital of South Bend)H-Index: 14
view all 6 authors...
Hypoplastic left heart syndrome (HLHS) and single ventricle (SV) remain a significant cause of cardiac deaths occurring in the first week of life. Their pathogenesis and seasonal frequency are still unknown. Therefore, we attempt to look at the genesis of the HLHS and SV in the context of territorial distribution as well as seasonality. A total of 193 fetuses diagnosed with HLHS and 92 with SV were selected. The frequency was analyzed depending on the year, calendar month, quarter and season (fa...
#1Yaping Zhou (Central South University Forestry and Technology)
#2Fuliang Cao (NFU: Nanjing Forestry University)H-Index: 21
Last. Feijun Luo (Central South University Forestry and Technology)H-Index: 25
view all 11 authors...
Several publications report that octacosanol (OCT) has different biological functions. This study was designed to evaluate the antifatigue effect and molecular mechanism of octacosanol (200 mg/(kg day)) in forced exercise-induced fatigue models of trained male C57BL/6 mice. Results showed that octacosanol ameliorated the mice's autonomic activities, forelimb grip strength, and swimming endurance, and the levels of liver glycogen (LG), muscle glycogen (MG), blood lactic acid (BLA), lactate dehydr...
#1Martin Broberg (UH: University of Helsinki)H-Index: 8
#2Johanna Hästbacka (Boston Children's Hospital)H-Index: 1
Last. Emmi Helle (Boston Children's Hospital)H-Index: 1
view all 3 authors...
#1Ansley M. Morrish (Children's Hospital at Westmead)
#2Janine Smith (USYD: University of Sydney)H-Index: 18
Last. Gillian M. Blue (USYD: University of Sydney)H-Index: 14
view all 9 authors...
Abstract 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...
#1Sukun Luo (HUST: Huazhong University of Science and Technology)H-Index: 8
#2Luyi Chen (HUST: Huazhong University of Science and Technology)
Last. Xuelian He (HUST: Huazhong University of Science and Technology)H-Index: 2
view all 10 authors...
Background: Congenital heart defects (CHDs) are the most common birth defects, and left heart hypoplasia (LHH) is a severe form of CHD and responsible for more than 20% cardiac deaths during the first week of life, however, its genetic causes remain largely elusive. Methods: Three families with fetal LHH were recruited. Genomic DNA from amniotic fluid or peripheral blood, and trio whole exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq) were performed. Results: All the th...
#1Heeyoung Seok (KU: Korea University)H-Index: 6
#2Rui Deng (Boston Children's Hospital)
Last. Da-Zhi Wang (Harvard University)H-Index: 57
view all 4 authors...
Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR-Cas9) is an ancient prokaryotic defense system that precisely cuts foreign genomic DNA under the control of a small number of guide RNAs. The CRISPR-Cas9 system facilitates efficient double-stranded DNA cleavage that has been recently adopted for genome editing to create or correct inherited genetic mutations causing disease. Congenital heart disease (CHD) is generally caused by genetic mutations su...
2 CitationsSource
#1McKay Mullen (Cardiovascular Institute of the South)
#2Angela Zhang (Cardiovascular Institute of the South)H-Index: 5
Last. Joseph C. Wu (Cardiovascular Institute of the South)H-Index: 123
view all 6 authors...
Congenital heart disease (CHD) is a multifaceted cardiovascular anomaly that occurs when there are structural abnormalities in the heart before birth. Although various risk factors are known to influence the development of this disease, a full comprehension of the etiology and treatment for different patient populations remains elusive. For instance, racial minorities are disproportionally affected by this disease and typically have worse prognosis, possibly due to environmental and genetic disp...