Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels. In this review, we present an updated view of the mechanism of ALK1 signaling, put forth a unified hypothesis to explain the cellular missteps that lead to AVMs associated with ALK1 deficiency, and discuss emerging roles for ALK1 signaling in diseases beyond HHT.

/pdf/alk1-signaling-in-development-and-disease-new-paradigms-41rlu13pql.pdf

ALK1 signaling in development and disease: new paradigms.

Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections.

About 10% of cases of hypertrophic cardiomyopathy (HCM) evolve into dilated cardiomyopathy (DCM) with unknown causes. We studied 11 unrelated patients (pts) with HCM who progressed to DCM (group A) and 11 who showed \"typical\" HCM (group B). Mutational analysis of the beta-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) genes demonstrated eight mutations affecting MYH7 or MYBPC3 gene, five of which were new mutations. In group A-pts, the first new mutation occurred in the myosin head-rod junction and the second occurred in the light chain-binding site. The third new mutation leads to a MYBPC3 lacking titin and myosin binding sites. In group B, two pts with severe HCM carried two homozygous MYBPC3 mutations and one with moderate hypertrophy was a compound heterozygous for MYBPC3 gene. We identified five unreported mutations, potentially \"malignant\" defects as for the associated phenotypes, but no specific mutations of HCM/DCM.

P2893 Hypertrophic cardiomyopathy: two homozygous cases with ?typical hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy

Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac β-myosin heavy chain (MYH7) gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C (MYBPC3) gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes. MYBPC3 and MYH7 mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that MYBPC3 mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of MYBPC3 and MYH7 mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of MYBPC3 and MYH7 were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both MYBPC3 and MYH7. These data provide evidence that MYBPC3 mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by MYH7 mutations.

/pdf/hypertrophic-cardiomyopathy-clinical-phenotype-is-rc9vrzjm2f.pdf

Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.

Motivation: High Throughput Sequencing (HTS) has enabled researchers to probe the human T cell receptor (TCR) repertoire, which consists of many rare sequences. Distinguishing between true but rare TCR sequences and variants generated by polymerase chain reaction (PCR) and sequencing errors remains a formidable challenge. The conventional approach to handle errors is to remove low quality reads, and/or rare TCR sequences. Such filtering discards a large number of true and often rare TCR sequences. However, accurate identification and quantification of rare TCR sequences is essential for repertoire diversity estimation. Results: We devised a pipeline, called Recover TCR (RTCR), that accurately recovers TCR sequences, including rare TCR sequences, from HTS data (including barcoded data) even at low coverage. RTCR employs a data-driven statistical model to rectify PCR and sequencing errors in an adaptive manner. Using simulations, we demonstrate that RTCR can easily adapt to the error profiles of different types of sequencers and exhibits consistently high recall and high precision even at low coverages where other pipelines perform poorly. Using published real data, we show that RTCR accurately resolves sequencing errors and outperforms all other pipelines.

/pdf/rtcr-a-pipeline-for-complete-and-accurate-recovery-of-t-cell-1vankakag9.pdf

RTCR: a pipeline for complete and accurate recovery of T cell repertoires from high throughput sequencing data

Pulmonary artery hypertension (PAH) is characterized as sustained elevation of pressure in the pulmonary vascular system attributable to a variety of causes. More than a dozen of genes have been previously proposed to be associated with PAH. In order to examine potential mutations of these genes in patients with PAH, we developed a targeted exome kit containing 22 PAH-associated genes for genetic screens of 80 unrelated patients with PAH. As results, we identified 16 different mutations in the BMPR2 gene and four different mutations in ACVRL1. However, no deleterious mutations were found in the remaining 20 genes. In the present report, we provided detailed characterization of the ACVRL1 mutations in four pedigrees, including two novel missense mutations (c.676G>A, p.V226M; c.955G>C, p.G319R) and two recurrent mutations (c.1231C>T, p.R411W; c.1450C>T, p.R484W). Furthermore, we showed that markedly reduced Smad1/5 phosphorylation levels and reduced activities of luciferase reporters in each of the four ACVRL1 mutants-transfected NIH-3T3 cells. Therefore, our findings demonstrated that missense mutations of ACVRL1 identified here significantly affected the BMP9 pathway implicating PAH pathogenesis. Detailed genotype-phenotype correlation analysis revealed initial symptoms of hereditary haemorrhagic telangiectasia (HHT) in some of the patients, suggesting the importance of sequencing molecular markers for early identification and intervention of individuals at risk for PAH and potential HHT.

Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture.

Background Dilated cardiomyopathy (DCM), which is a major cause of heart failure, is a primary cardiac muscle disease with high morbidity and mortality rates. DCM is a genetically heritable disease and more than 10 gene ontologies have been implicated in DCM. CDH2 encodes N-cadherin and belongs to a superfamily of transmembrane proteins that mediate cell–cell adhesion in a calcium-dependent manner. Deficiency of CDH2 is associated with arrhythmogenic right ventricular cardiomyopathy (OMIM: 618920) and agenesis of the corpus callosum, cardiac, ocular, and genital syndrome (OMIM: 618929). However, there have been no reports of isolated DCM associated with CDH2 deficiency. Methods We performed whole exome sequencing in a 12-year-old girl with non-syndromic DCM and her unaffected parents. Variants in both known DCM-related genes and novel candidate genes were analyzed and pathogenicity confirmation experiments were performed. Results No pathogenic/likely pathogenic variant in known DCM-related genes was identified in the patient. We found a de novo variant in a candidate gene CDH2 in the patient, namely, c.474G>C/p.Lys158Asn (NM_001792.5). This variant has not been reported in the ClinVar or Human Gene Mutation Database (HGMD). CDH2 p.Lys158Asn was found in the conserved domain of N-cadherin, which is associated with the hydrolysis of the precursor segment and interference with adhesiveness. Furthermore, we tested the expression and efficiency of cell–cell adhesion while overexpressing the CDH2 Lys158Asn mutant and two previously reported variants in CDH2 as positive controls. The adhesion efficiency was considerably reduced in the presence of the mutated CDH2 protein compared with wild-type CDH2 protein, which suggested that the mutated CDH2 protein's adhesion capacity was impaired. The variant was probably pathogenic after integrating clinical manifestations, genetic analysis, and functional tests. Conclusion We identified a CDH2 variant in DCM. We observed a new clinical symptom associated with N-cadherin deficiency and broadened the genetic spectra of DCM.

Identification of a novel variant in N-cadherin associated with dilated cardiomyopathy

The invention discloses a pulmonary hypertension virulence gene ACVRL1 mutation site and an application thereof. The amino acid sequence of a protein provided by the invention is sequence 4. The DNA molecule of the protein is coded and the nucleotide sequence of the DNA molecule is sequence 2. The experiment shows that the novel ACVRL1 gene mutation site is related to the pulmonary hypertension, by means of detecting whether the novel gene mutation site is the mutation site, whether the sample to be tested suffers from pulmonary hypertension can be predicted; and the novel gene mutation site can be used as a target for treating the pulmonary hypertension, and a new therapy pathway for researching the pulmonary hypertension drugs can be provided. The cell experiment verifies that the ACVRL1 gene mutation site is capable of reducing the SMAD1 and SMAD5 protein phosphorylation and/or increasing the BMP transcriptional activity in the cell.

Pulmonary hypertension virulence gene ACVRL1 mutation site and application thereof

OBJECTIVE
To explore the clinical phenotype and genetic features of a child with dilated cardiomyopathy (DCM).


METHODS
Clinical data of the child who had presented at the Zhengzhou Children's Hospital on April 28, 2020 was collected. Trio-whole exome sequencing (trio-WES) was carried out for the child and her parents, and candidate variants were validated by Sanger sequencing. "FHL2" was taken as the key word to retrieve related literature from January 1, 1997 to October 31, 2021 in the PubMed database and was also searched in the ClinVar database as a supplement to analyze the correlation between genetic variants and clinical features.


RESULTS
The patient was a 5-month-old female infant presented with left ventricular enlargement and reduced systolic function. A heterozygous missense variant c.391C>T (p.Arg131Cys) in FHL2 gene was identified through trio-WES. The same variant was not detected in either of her parents. A total of 10 patients with FHL2 gene variants have been reported in the literature, 6 of them had presented with DCM, 2 with hypertrophic cardiomyopathy (HCM), and 2 with sudden unexplained death (SUD). Phenotypic analysis revealed that patients with variants in the LIM 3 domain presented hypertrophic cardiomyopathy and those with variants of the LIM 0~2 and LIM 4 domains had mainly presented DCM. The c.391C>T (p.Arg131Cys) has been identified in a child with DCM, though it has not been validated among the patient's family members. Based on the guidelines of the American College of Medical Genetics and Genomics, the c.391C>T(p.Arg131Cys) variant was re-classified as likely pathogenic (PS2+PM2_Supporting+PP3+PP5).


CONCLUSION
The heterozygous missense variant of c.391C>T (p.Arg131Cys) in the FHL2 gene probably predisposed to the DCM in this child, which has highlighted the importance of WES in the clinical diagnosis and genetic counseling.

[A case of dilated cardiomyopathy caused by FHL2 gene variant and a literature review].

The poor survival rate of small cell lung cancer (SCLC) is mainly related to the condition that patients with SCLC often have good responses to first-line chemotherapy initially, but later on, most of these patients relapse rapidly due to resistance to further treatment. In this study, we attempted to analyze whole-exome sequencing data based on the largest sample size to date, to develop a classifier to predict whether a patient will be chemorefractory or chemosensitive and to explicate the risk of recurrence that affects the prognosis of patients. We showed the different characteristics of somatic mutational signatures, somatic mutation genes, and distinct genome instability between chemorefractory and chemosensitive SCLC patients. Amplified mutations in the chemosensitive group inhibited the regulation of the cell cycle process, transcription factor binding, and B-cell differentiation. Analysis of deletion mutation also suggested that detection of the chromosomal-level variation might influence our treatment decisions. Higher PD-L1 expressions (based on TPS methods) were mostly present among chemosensitive patients (p = 0.026), while there were no differences in PD-L1 expressions (based on CPS methods) and CD8+ TILs between the two groups. According to the model determined by logistic regression, each sample was endowed with a predictive probability value (PV). The samples were divided into a high-risk group (>0.55) and a low-risk group (≤0.55), and the survival analysis showed obvious differences between the two groups. This study provides a reference basis to translate this knowledge into practice, such as formulating personalized treatment plans, which may benefit Chinese patients with SCLC.

/pdf/whole-exome-sequencing-uncovers-specific-genetic-variation-1i4w3owv.pdf

Whole-Exome Sequencing Uncovers Specific Genetic Variation Difference Based on Different Modes of Drug Resistance in Small Cell Lung Cancer

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