• cardiology
• genetics
• genomics

• Animals
• Cats
• High-Throughput Nucleotide Sequencing
• Cat Diseases/genetics
• Male
• Female
• Cardiomyopathy, Hypertrophic/genetics
• Cardiomyopathy, Hypertrophic/veterinary
• Pedigree
• Genetic Variation
• Genetic Predisposition to Disease
• Cardiomyopathy, Restrictive/genetics
• Cardiomyopathy, Restrictive/veterinary
• Cardiomyopathies/genetics
• Cardiomyopathies/veterinary
• Phenotype

• 1903448 Biotechnology and Biological Sciences Research Council
• S18-693-731 Petplan Charitable Trust

• Functional annotation and colocalization
• Genetic correlation and overlap
• Genome-wide association studies (GWAS)
• Pleiotropic genes

• Humans
• Mental Disorders/genetics
• Mental Disorders/complications
• Genome-Wide Association Study
• Genetic Pleiotropy/genetics
• Brain/metabolism
• Heart Diseases/genetics
• Polymorphism, Single Nucleotide/genetics
• Genetic Predisposition to Disease
• Mendelian Randomization Analysis
• Animals

• cardiomyopathies
• long non-coding RNAs
• micro-RNAs
• non-coding RNAs

• alcohol septal ablation
• heart failure
• hypertrophic obstructive cardiomyopathy
• mavacamten
• mitral valve regurgitation
• septal myectomy
• systolic anterior motion

• PRKAG2 cardiomyopathy
• cardiac magnetic resonance
• genetic test
• hypertrophic cardiomyopathy
• left ventricular hypertrophy

• Humans
• Mutation, Missense
• Adult
• Hypertrophy, Left Ventricular/genetics
• Female
• AMP-Activated Protein Kinases/genetics
• Electrocardiography
• Male
• Pedigree

• NOTCH3
• filamin a
• genetics
• thoracic aortic aneurysm

• Humans
• Male
• Female
• Aortic Aneurysm, Thoracic/genetics
• Aortic Aneurysm, Thoracic/diagnosis
• Mosaicism
• Adult
• Middle Aged
• Germ-Line Mutation
• Genetic Predisposition to Disease
• Receptor, Notch3/genetics
• Fibrillin-1/genetics
• Case-Control Studies
• Phenotype
• Filamins/genetics
• Risk Factors
• High-Throughput Nucleotide Sequencing
• Adipokines

• R01 HL130113 NHLBI NIH HHS
• R01 HL152063 NHLBI NIH HHS
• R01 NS035129 NINDS NIH HHS
• UG3 NS132144 NINDS NIH HHS
• National Heart Lung and Blood Institute (NHLBI)
• National Institute of Neurological Disorders and Stroke
• Howard Hughes Medical Institute
• National Institutes of Health

• genetic testing
• cardiovascular diseases

• Humans
• Arrhythmias, Cardiac/diagnosis
• Arrhythmias, Cardiac/genetics
• Cardiomyopathies/diagnosis
• Cardiomyopathies/genetics
• Genetic Testing
• Death, Sudden, Cardiac/etiology
• Long QT Syndrome/diagnosis

• HCM-associated variants
• NGS
• diagnosis
• genetics
• hypertrophic cardiomyopathy
• miRNA
• missing heritability
• polygenic risk score

• Russian Science Foundation

• Genetic diagnosis
• Intron characterization
• Intronic position +9 and −9
• Intronic regions flanking exons
• Intronic variants
• Next-generation sequencing (NGS)
• WES
• Whole exome sequencing

• No. 81902139 National Natural Science Foundation of China
• No. 81972000 National Natural Science Foundation of China
• No. 82172348 National Natural Science Foundation of China
• No. YDZX20193502000002 the key medical and health projects of Xiamen
• No. shslczdzk03302 the constructing project of clinical key disciplines in Shanghai

• arrhythmia
• cardiomyopathy
• cardiovascular diseases
• congenital heart disease
• hypercholesterolemia
• hypertension
• non-coding variants

• Humans
• Cardiovascular Diseases/genetics
• Genome-Wide Association Study
• Polymorphism, Single Nucleotide/genetics
• Phenotype
• MicroRNAs/genetics

• cardiomyopathy
• enhancers
• intronic variants
• noncoding variants
• promoters
• untranslated regions

• K08 HL145135 NHLBI NIH HHS
• NHLBI

• Z-disk protein
• alpha-actinin
• cardiomyopathy
• desmin (DES)
• filamin C (FLNC)
• myopalladin (MYPN)
• pathogenic variant
• titin (TTN)

• Oxford Nanopore
• hypertrophic cardiomyopathy
• long-read sequencing
• sarcomeric protein genes

• Humans
• Nanopore Sequencing
• Carrier Proteins/genetics
• Mutation
• Cardiomyopathy, Hypertrophic/genetics
• Troponin T/genetics

• 22-24-01164 Russian Science Foundation

• genome-wide association studies
• cardiovascular genetics
• genetic markers

• Alleles
• Cholesterol, LDL
• Genome-Wide Association Study
• Humans
• Lipids
• Whole Genome Sequencing

• R01 HL113323 NHLBI NIH HHS
• R01 HL127564 NHLBI NIH HHS
• R01 HL163560 NHLBI NIH HHS
• R01 HL105756 NHLBI NIH HHS
• K08 HL141601 NHLBI NIH HHS
• R01 HL140570 NHLBI NIH HHS
• R01 HL151152 NHLBI NIH HHS
• R03 HL154284 NHLBI NIH HHS
• R01 HL135242 NHLBI NIH HHS
• R01 HL090682 NHLBI NIH HHS
• K01 HL135405 NHLBI NIH HHS
• R01 HL139731 NHLBI NIH HHS
• R35 CA197449 NCI NIH HHS
• P30 ES010126 NIEHS NIH HHS
• K01 AG059898 NIA NIH HHS
• R01 HL121007 NHLBI NIH HHS
• U01 DK085524 NIDDK NIH HHS
• U19 CA203654 NCI NIH HHS
• R01 HL151283 NHLBI NIH HHS
• R01 HL148565 NHLBI NIH HHS
• R01 HL113338 NHLBI NIH HHS
• R01 HL153805 NHLBI NIH HHS
• R01 MH078111 NIMH NIH HHS
• S10 OD026880 NIH HHS
• R01 HL142711 NHLBI NIH HHS
• R35 HL135818 NHLBI NIH HHS
• U01 HL072515 NHLBI NIH HHS
• P01 HL045522 NHLBI NIH HHS
• I01 CX001737 CSRD VA
• P30 DK020541 NIDDK NIH HHS
• S10 OD030463 NIH HHS
• R01 MH078143 NIMH NIH HHS
• U01 HL072507 NHLBI NIH HHS
• R01 HL093093 NHLBI NIH HHS
• R01 HL087263 NHLBI NIH HHS
• R01 HL157635 NHLBI NIH HHS
• T32 CA154274 NCI NIH HHS
• U01 HG009088 NHGRI NIH HHS
• I01 BX005831 BLRD VA
• R01 MH083824 NIMH NIH HHS
• R01 HL148050 NHLBI NIH HHS
• R01 AG018728 NIA NIH HHS
• U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)

Subjective or objective subtle cognitive decline (SCD) is considered the preclinical manifestation of Alzheimer's disease (AD), which is a potentially crucial window for preventing or delaying the progression of the disease.

To explore the potential mechanism of disease progression and identify relevant biomarkers, we comprehensively assessed the peripheral blood transcriptomic alterations in SCD, covering lncRNA, mRNA, and miRNA.

Dysregulated protein-coding mRNA at both gene and isoform levels implicated impairment in the type I interferon signaling pathway in SCD. Specifically, this pathway was regulated by the transcription factor STAT1 and ncRNAs NRIR and has-miR-146a-5p. The miRNA-mRNA-lncRNA co-expression network revealed hub genes for the interferon module. Individuals with lower interferon signaling activity and lower expression of a hub gene STAT1 exhibited a higher conversion rate to mild cognitive impairment (MCI).

Our findings illustrated the down-regulation of interferon signaling activity would potentially increase the risk of disease progression and thus serve as a pre-disease biomarker.

This work was partly supported by National Key R&D Program of China (2020YFA0712403), National Natural Science Foundation of China (61932008), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), the 111 Project (No. B18015) of China, Greater Bay Area Institute of Precision Medicine (Guangzhou) (Grand No. IPM21C008), Natural Science Foundation of Shanghai (21ZR1403200), and Shanghai Center for Brain Science and Brain-Inspired Technology.

This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives.

A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool.

A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), MYH7 versus MYBPC3 cohorts (8.2 years; p<0.0001) and individuals with multiple versus single variants (7.0 years; p<0.0002). Overall, disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs 55%; p=0.003).

This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study.

• cardiomyopathy, hypertrophic
• genetic diseases, inborn
• systematic reviews as topic

• RNA splicing
• congenital hypothyroidism
• intron variants
• splice-site mutation
• thyroid dyshormonogenesis

• Congenital Hypothyroidism/genetics
• Female
• Humans
• Male
• Mutation
• RNA Splice Sites/genetics
• RNA Splicing
• Sulfate Transporters/genetics
• Symporters/genetics

• Genetic heart disease
• Hypertrophic cardiomyopathy
• Molecular autopsy
• NGS
• Next-generation sequencing
• Sudden cardiac death

• Genetic variants
• Hypertrophic cardiomyopathy
• Left ventricular hypertrophy
• Sarcomeric genes
• Sudden cardiac death

Lynch Syndrome (LS) is caused by germline mutations in the DNA mismatch repair (MMR) genes with mutations in MLH1 accounting for ~40% of LS‐related alterations.

MSK‐IMPACT analysis was performed on peripheral blood from a patient with early‐ onset colorectal cancer. Subsequently PCR and sequencing was performed to characterize the insertion. Immunohistochemistry for MMR genes and MLH1 promoter methylation were analyzed on patient's tumor.

MSK‐IMPACT germline testing revealed an insertion into c.588+8_588+9 of MLH1 intron 7. The insertion was further characterized as an AluSx‐like element with ~115 bp in length. Functional studies demonstrated that the AluSx‐like element led to complete disruption of mRNA splicing and probably resulted in transcriptional termination at the poly (A) region of the AluSx‐like insertion.

The insertion of a truncated AluSx like element into MLH1 intron 7 results in aberrant splicing and transcription, thereby causing Lynch syndrome. This study confirms that retrotransposon insertions may be an important mechanism for cancer predisposition.

• MLH1
• AluSx
• Lynch syndrome
• splicing

• hcm, hypertrophic cardiomyopathy
• lvh, left ventricular hypertrophy
• snp, single-nucleotide polymorphism

• Animals
• Cardiomyopathy, Hypertrophic/genetics
• Cardiomyopathy, Hypertrophic/veterinary
• Carrier Proteins/genetics
• Cats
• Haplotypes
• Humans
• Macaca mulatta/genetics
• Mutation

• P51 OD011107 NIH HHS

• VCL
• cardiomyopathy gene panel testing
• dilated cardiomyopathy
• dilated cardiomyopathy genetics
• pediatric cardiomyopathy
• risk allele
• vinculin
• vinculin loss of function

• Hypertrophic cardiomyopathy
• Likely pathogenic variant
• Miocardiopatia hipertrófica
• Mutação do gene TCAP
• TCAP mutation
• Telethonin
• Teletonina
• Titin-cap
• Variante provavelmente patogénica

• Estudo genético
• Genetic testing
• Hypertrophic cardiomyopathy
• Intronic variant
• MYBPC3
• Miocardiopatia hipertrófica
• Variante intrónica
• Whole-genome sequencing

• Genetic Predisposition to Disease
• Genomics/methods
• Humans
• Pharmacogenomic Variants
• Precision Medicine/methods

• Z99 HG999999 Intramural NIH HHS

Myostatin, a negative regulator of skeletal muscle mass in animals, has been shown to play a role in determining muscular hypertrophy in several livestock species, and a high degree of polymorphism has been previously reported for this gene in humans and cattle. In this study, we provide a characterization of the myostatin gene in the dromedary (Camelus dromedarius) at the genomic, transcript and protein level. The gene was found to share high structural and sequence similarity with other mammals, notably Old World camelids. 3D modeling highlighted several non-conservative SNP variants compared to the bovine, as well as putative functional variants involved in the stability of the myostatin dimer. NGS data for nine dromedaries from various countries revealed 66 novel SNPs, all of them falling either upstream or downstream the coding region. The analysis also confirmed the presence of three previously described SNPs in intron 1, predicted here to alter both splicing and transcription factor binding sites (TFBS), thus possibly impacting myostatin processing and/or regulation. Several putative TFBS were identified in the myostatin upstream region, some of them belonging to the myogenic regulatory factor family. Patterns of SNP distribution across countries, as suggested by Bayesian clustering of the nine dromedaries using the 69 SNPs, pointed to weak geographic differentiation, in line with known recurrent gene flow at ancient trading centers along caravan routes. Myostatin expression was investigated in a set of 8 skeletal muscles, both at transcript and protein level, via Digital Droplet PCR and Western Blotting, respectively. No significant differences were observed at the transcript level, while, at the protein level, the only significant differences concerned the promyostatin dimer (75 kDa), in four pair-wise comparisons, all involving the tensor fasciae latae muscle. Beside the mentioned band at 75 kDa, additional bands were observed at around 40 and 25 kDa, corresponding to the promyostatin monomer and the active C-terminal myostatin dimer, respectively. Their weaker intensity suggests that the unprocessed myostatin dimers could act as important reservoirs of slowly available myostatin forms. Under this assumption, the sequential cleavage steps may contribute additional layers of control within an already complex regulatory framework.

• 3D protein comparative modeling
• Camelus dromedarius
• Digital Droplet PCR
• Next Generation Sequencing
• Single Nucleotide Polymorphisms
• Western Blot
• myostatin
• skeletal muscle

• Cardiomyopathy, Dilated/diagnosis
• Cardiomyopathy, Dilated/genetics
• Cardiomyopathy, Hypertrophic/diagnosis
• Cardiomyopathy, Hypertrophic/genetics
• Female
• Genetic Markers
• Genetic Testing
• High-Throughput Nucleotide Sequencing
• Humans
• Male
• Middle Aged
• Mutation
• Sequence Analysis, DNA/methods
• Exome Sequencing/methods

• 01121616 Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (HMRF)
• 01221616 Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (HMRF)
• Hong Kong Research Grant Council: Theme based research scheme (T12-705/11)