MYH7 Research Articles

MYH9-related disorder with sole presentation of end-stage kidney disease and long-term, recurrence-free living after living donor renal transplantation: a case report.

MYH9-related disorders are a group of autosomal dominant disorders caused by mutations in MYH9, and are characterized by thrombocytopenia, sensorineural hearing loss, cataracts, and renal failure. Here, we report a case of chronic renal failure due to MYH9-related disorder with renal symptoms in a patient who underwent living-donor renal transplantation. The patient was diagnosed with proteinuria during a health checkup at the age of 12years. Her renal function gradually deteriorated, and hemodialysis was initiated at 34years of age. No definitive diagnosis of renal disease was made through renal biopsy. At the age of 35, she underwent living-donor renal transplantation from her mother as the donor. Six years after transplantation, her renal function remained stable, and no evidence of recurrent nephritis was found during renal biopsies. The family history revealed that her father, uncle, and younger brother had end-stage kidney disease. Genetic testing revealed a mutation (p.E1653D) related to the MYH9 gene. As her father had a history of renal biopsy and was diagnosed with focal segmental glomerulosclerosis (FSGS), we diagnosed chronic renal failure due to FSGS associated with MYH9 disorder. There were no findings suggestive of hearing loss, cataracts, or thrombocytopenia in the recipient or their family members with renal failure, and no symptoms other than renal failure were noted.

Complex genotype–phenotype correlation of MYH11: new insights from monozygotic twins with highly variable expressivity and outcomes

BackgroundThoracic aortic aneurysm/dissection (TAAD) and patent ductus arteriosus (PDA) are serious autosomal-dominant diseases affecting the cardiovascular system. They are mainly caused by variants in the MYH11 gene, which encodes the heavy chain of myosin 11. The aim of this study was to evaluate the genotype–phenotype correlation of MYH11 from a distinctive perspective based on a pair of monozygotic twins.MethodsThe detailed phenotypic characteristics of the monozygotic twins from the early fetal stage to the infancy stage were traced and compared with each other and with those of previously documented cases. Whole-exome and Sanger sequencing techniques were used to identify and validate the candidate variants, facilitating the analysis of the genotype–phenotype correlation of MYH11.ResultsThe monozygotic twins were premature and presented with PDA, pulmonary hypoplasia, and pulmonary hypertension. The proband developed heart and brain abnormalities during the fetal stage and died at 18 days after birth, whereas his sibling was discharged after being cured and developed normally post follow-up. A novel variant c.766 A > G p. (Ile256Val) in MYH11 (NM_002474.2) was identified in the monozygotic twins and classified as a likely pathogenic variant according to the American College of Medical Genetics/Association for Molecular Pathology guidelines. Reviewing the reported cases (n = 102) showed that the penetrance of MYH11 was 82.35%, and the most common feature was TAAD (41.18%), followed by PDA (22.55%), compound TAAD and PDA (9.80%), and other vascular abnormalities (8.82%). The constituent ratios of null variants among the cases with TAAD (8.60%), PDA (43.8%), or compound TAAD and PDA (28.6%) were significantly different (P = 0.01). Further pairwise comparison of the ratios among these groups showed that there were significant differences between the TAAD and PDA groups (P = 0.006).ConclusionThis study expands the mutational spectrum of MYH11 and provides new insights into the genotype–phenotype correlation of MYH11 based on the monozygotic twins with variable clinical features and outcomes, indicating that cryptic modifiers and complex mechanisms beside the genetic variants may be involved in the condition.

Influence of Clinical Aspects and Genetic Factors on Feline HCM Severity and Development.

Hypertrophic cardiomyopathy (HCM), which is associated with thickening of the left ventricular wall, is one of the most common heart pathologies in cats. This disease has a hereditary etiology and is primarily related to mutations in the MYBPC3 and MYH7 genes. This study aims to determine the effect of the presence of heterozygosity or homozygosity for the p. A31P mutation (c.91G>C) in the MYBPC3 gene in cats (Maine Coon) of different ages referring to the HCM severity and development, and to compare echocardiographic data and various clinical aspects for the most objective detection of disease in cats of different breeds. The incidence of HCM was 59% of the 103 cases of heart disease in cats in this study. In 23 cats diagnosed with HCM, cats heterozygous for the mutation accounted for 34%, and homozygous cats accounted for 26%. Cats homozygous for this mutation had moderate to severe HCM, suggesting an association with high penetrance of HCM and a significant risk of cardiac death in this group. The penetrance of the heterozygous type was lower than that of the homozygous genotype. This study also indicates that HCM has some age-related penetrance. The disease did not occur in the study group of cats aged up to 1 year, whereas at the age of 7 and older, the percentage of animals diagnosed with HCM was the highest and amounted to 44.3% of the total number of studied cats with HCM.

Comparison of MYOCYTER and MUSCLEMOTION in the analysis of Induced Pluripotent Stem Cell Derived Cardiomyocyte Contractility

Patient-specific induced pluripotent stem cells (iPSCs) differentiated into cardiomyocytes (CMs) offer tremendous opportunities for cardiac disease modeling and advancements in precision medicine. There is a need for technologies that allow noninvasive and precise measurements of CM function, such as contractility, to increase throughput for drug screening and testing efforts. Hypoplastic Left Heart Syndrome (HLHS) is a rare and complex congenital heart defect characterized by hypoplasia of the left ventricle, proximal aorta, as well as stenosis or atresia of the mitral and/or aortic valves. Previously it was demonstrated that iPSC-CMs from an HLHS patient with a genetic variant in the alpha myosin heavy chain ( MYH6 gene) exhibited an impaired cardiomyocyte phenotype (dysmorphic sarcomere structure, compensatory expression of MYH7, and altered contractility). Gene editing using CRISPR/Cas9 rescued the phenotype, demonstrating the utility of MYH6 iPSC-CMs as a useful disease model for HLHS. Critical parameters of CM function include contraction and relaxation, assessing systolic and diastolic dysfunction, respectively, in iPSC-CMs. The aim of this study is to compare features from two open-source macros for ImageJ: MYOCYTER and MUSCLEMOTION. MYOCYTER improves upon previous plugins available by allowing for users to select parameters. Both methods allow measurement of movement from high-speed movies. MYOCYTER enables the user to select an optimal threshold, size, and cell count to minimize disturbances such as cellular fragments, background noise, and floating bubbles, to maximize precision during analysis. MUSCLEMOTION allows rapid and easy measurement of movement from high- speed videos and can measure and compare relative or absolute parameters. This study will determine whether a systolic or diastolic dysfunction phenotype is observed under different magnification settings and evaluate the effect of dosing with pharmaceutical compounds. Finally, benefits and drawbacks of both macros will be investigated. Children's Research Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Retinoic acid modulation guides human-induced pluripotent stem cell differentiation towards left or right ventricle-like cardiomyocytes

Background: Cardiomyocytes (CMs) induced from human induced pluripotent stem cells (hiPSCs) by traditional methods are a mix of atrial and ventricular CMs and other non-cardiomyocytes. Retinoic acid (RA) plays an important role in regulation of the spatiotemporal development of the embryonic heart. Aim: Create engineered heart tissue (EHT) with left and right ventricular phenotype from hiPSCs by intervening with specific concentrations of RA during hiPSC differentiation towards CM. Methods: hiPSC were derived by reprogramming skin fibroblasts and erythroid progenitors. Different concentrations of RA (Control without RA, LowRA with 0.05 μM and HighRA with 0.1 μM) were administered during third to sixth days of the differentiation process. EHTs were generated by assembling CMs derived from hiPSC (hiPSC-CM) at high cell density in a low collagen hydrogel. EHTs were further matured and grown in a customized biomimetic tissue culture system, that provides continuous electrical stimulation, medium agitation and stretch. Finally, RNA extraction and tissue fixation were performed on CMs and EHTs for RT-qPCR and immunofluorescence staining analysis, while RNA sequencing was conducted on EHTs to examine how RA affects gene expression associated with function and structure of EHTs. Results: HighRA-hiPSC-CMs exhibited highest expression of maturity genes MYH7 and cTnT. The expression of TBX5, NKX2.5 and CORIN, which are transcription factors associated with left ventricular development, was also the highest in the HighRA-hiPSC-CM. The expression of TBX5 and NKX2.5 was also found to be highest in the HighRA-EHTs, while expression of right ventricular transcrition factors TBX20 and ISL1 was highest in control-EHTs. RNAseq of EHTs showed augmented extracellular matrix gene expression in HighRA-EHTs. The HighRA-EHTs were functionally most similar to left ventricle with the highest contraction force, the lowest beating frequency, and the highest sensitivity to hypoxia and isoprenaline. Conclusion: By interfering with the differentiation process of hiPSC with a specific concentration of RA at a specific time, we were able to successfully induce CMs and EHT with a phenotype similar to that of the left ventricle or right ventricle. Our research paves the way for future studies on in vitro left ventricular or right ventricular function, personalized drug screening, and precision medicine. German Center for Cardiovascular Research (DZHK81Z0600207 to D.M. and P.S.) China Scholarship Council (CSC202108410141) and Henan Provincial Medical Science and Technology Research Project. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Extracellular vesicles characterization in patients with hypertrophic cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is diagnosed according to the presence of morphological and functional traits of the heart, often in the presence of genetic mutations. A specific biomarker assessing the aetiopathology of this condition is lacking. Extracellular vesicles (EVs), small particles released by all cells into biological fluids, hold promise as diagnostic and prognostic tools for cardiac diseases. We aim at characterising plasma-derived EVs isolated from 18 consecutive HCM patients and 13 healthy volunteers (CTR). Methods: HCM underwent echocardiographic assessment and genetic testing evaluating 200 genes (NGS). EVs were isolated via ultracentrifugation from platelet-free plasma. Quantitative and qualitative assessments of EVs were performed by nanoparticle tracking analysis and transmission electron microscopy. FACS analysis was used to characterize EV subpopulations. Data are expressed as median and interquartile ranges. Results: Most patients were male (70.8% HCM and 54% CTR) with a median age of 61 (52.5-71) years (HCM) and 47 (44-52) (CTR). Missense mutations in the MYH7 gene were the most found in HCM. The median maximum wall thickness in HCM was 16 mm (15-19) vs 8 mm (7-9) in CTR. No differences were found in EV concentrations between HCM and CTR, respectively, 3.6*109 EV/ml/cell count (2*109-5*109) and 5*10⁹ EV/ml/cell count (4*109-6*109). However, EV concentration was positively associated with the sudden cardiac death risk score in HCM (r= 0.63). Among the EVs positive for CFSE (a specific dye for EVs), those released from platelets, progenitor endothelial cells and neutrophils were increased in HCM patients vs CTR, respectively, by 1.7-, 1.5- and 1.1-fold. A strong negative association (r= -0.74) was found between progenitor endothelial cell-derived EVs and the E/E’ ratio of diastolic function, a strong predictor of first cardiac events. Conclusions: HCM patients present a peculiar phenotypic pattern of EVs that associates which diastolic function and sudden cardiac death.

Role of cardiac magnetic resonance imaging in assessing the risk of various myocardial remodeling types in left ventricular noncompaction: genetic analysis data

Aim. To analyze contrast-enhanced cardiac magnetic resonance imaging (MRI) in patients with phenotypic manifestations of left ventricular non-compaction (LVNC) and related genetic mutations, as well as to determine the relationship between mutations and types of left ventricular (LV) remodeling and with a number of other morphological and functional cardiac parameters.Material and methods. From the registry of patients with LVNC and their relatives, patients with morphological signs of LVNC and 4 related mutations (MYH7, MYBPC3, TTN, and desmin genes (DES, DSG2, DSP and DSC2)). All patients underwent contrast-enhanced cardiac MRI, based on which the type of LV remodeling was determined.Results. The study included 44 patients who, according to genetic analysis, had mutations in sarcomeric genes responsible for LVNC development. In each patient, the type of LV remodeling was determined based on cardiac MRI results. We found that if patients with LVNC have mutations in the MYBPC3 and TTN genes, the chance of LV dilatation remodeling is significantly higher. On the contrary, in the presence of a DES gene mutation, the probability of this LV remodeling is lower, and milder morphological manifestations of LVNC are noted.Conclusion. The combination of cardiac MRI data and genetic analysis improves the morphological and functional stratification of patients with LVNC.

Fetal Dilated Myocardiopathy – Case Report: Association with a heterozygous mutation in MYH7 gene

We report a case of dilated myocardiopathy with ascites and cardiac dysfunction detected at 20 weeks’ gestation. Baby was born at 33 weeks and 6 days, weighing 2530g, delivered by cesarean section and admitted to NICU. Postnatal echocardiography confirmed biventricular severe dysfunction, need of ventilatory support, vasoactive drugs, and prostaglandins. He was investigated for metabolic, infectious, and viral diseases with no positive results. After 6 weeks, he was transferred to a transplant center. Exome sequence showed a heterozygous mutation in the MYH7 gene (OMIN-160760.0028).

Diagnosis and treatment of arrhythmogenic cardiomyopathy in children

Objective: To summarize the clinical manifestations, experiences in diagnosis and treatment of arrhythmogenic cardiomyopathy (ACM) in children. Methods: A retrospective analysis of the clinical manifestations, laboratory tests, radiological features, treatment and follow-up results was conducted in 11 children diagnosed with ACM at the center of congenital heart disease, Beijing anzhen hospital from May 2010 to March 2022. Results: A total of 11 patients aged 2 to 16 years, including 5 males and 6 females were diagnosed with ACM. The clinical manifestations included decreased activity tolerance (7 patients), heart failure (4 patients), syncope or sudden death (3 patients), palpitation (3 patients), and chest tightness and pain (3 patients). Electrocardiogram showed right bundle branch block in 9 cases, paroxysmal ventricular tachycardia in 4 cases, frequent premature ventricular contraction in 4 cases, ventricular pre-excitation in 1 case, left bundle branch block in 1 case, and first degree atrioventricular block in 2 cases. Echocardiography showed enlargement of the right heart, widening of the right ventricular outflow tract, and thinning and bulging of the local wall of the right ventricle with reduced pulsation. Ventricular thrombosis was found in 2 cases. Six children underwent cardiac magnetic resonance imaging, which mainly showed severe enlargement of the right heart, thin free wall of the right ventricle, decreased right heart function, enhanced right ventricular myocardium, and formation of right ventricular aneurysm. Two children underwent myocardial biopsy examination and presented with typical pathological changes of ACM. Genetic tests in five patients revealed DSG2 gene mutation in 2 cases, PKP2 gene mutation in 2 cases, and MYH6 gene mutation in 1 case. All patients received anti heart failure treatment and antiarrhythmic drugs. Two children received anticoagulant treatment due to ventricular thrombosis. Radiofrequency ablation was performed in 2 patients. Glenn procedure was performed in 4 patients, and heart transplantation was performed in 1 patient due to progressive heart failure. The follow-up period ranged from 6 months to 12 years. Two cases died of right heart failure, 6 cases had different degrees of heart failure, 1 case had intermittent chest tightness and pain, and 2 cases were stable. Conclusions: ACM is a progressive genetic cardiomyopathy characterized by decreased activity tolerance, cardiac failure and arrhythmia in pediatric patients. The diagnosis is mainly based on clinical manifestations, electrocardiogram, cardiac imaging changes, and genetic testing. Early detection, diagnosis, and personalized treatment can improve the prognosis.

Abstract P160: Prevalence of Genetic Dilated Cardiomyopathy: A Systematic Literature Review

Background: Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation worldwide. Many cases of DCM are due to genetic or idiopathic etiology. Two prominent contributors to genetic DCM (gDCM) are the TTN and MYH7 genes, which encode proteins associated with DCM etiology. Purpose: This study aimed to synthesize the published literature on the global prevalence of adult and pediatric gDCM within the clinical DCM population and the general population. Methods: A systematic review was conducted by searching MEDLINE® and Embase from database inception to 09/19/2022. We included observational studies reporting the prevalence of gDCM within any population; prevalence of TTN and MYH7 mutations were also extracted. Excluded were studies using family history as a proxy for gDCM. Median with interquartile range (IQR) or mean with standard deviation (SD) weighted by sample size (in cases of calculations with <10 studies) were used to summarize the data. Results: Of 2,720 identified abstracts, 57 studies were included in the review. Among the adult or mixed (adults and children) DCM population in any country, median prevalence was 21.0% for overall DCM-related genetic mutations, 11.4% for TTN mutations, and 3.2% for MYH7 mutations ( Table ). The prevalence of pediatric gDCM within the DCM population was similar (weighted mean: 21.3%). Data on prevalence of gDCM within the general population were scarce. Conclusion: This study highlights the variable prevalence of gDCM reported across different populations and settings. The current evidence may underestimate the genetic causes due to technical limitations in genetic testing and limited screening. Accurately determining the prevalence of gDCM is critical for identifying high-risk populations, developing targeted prevention strategies for disease complications, and improving outcomes; epidemiological studies using long-read sequencing techniques and large cohort datasets with genotype-phenotype correlation analyses are needed.

Genetic Testing Yield and Clinical Characteristics of Hypertrophic Cardiomyopathy in Understudied Ethnic Groups: Insights From a New Zealand National Registry.

Aotearoa/New Zealand has a multiethnic population. Patients with hypertrophic cardiomyopathy (HCM) are enrolled in the national Cardiac Inherited Diseases Registry New Zealand. Here, we report the characteristics of Cardiac Inherited Diseases Registry New Zealand HCM probands with and without pathogenic or likely pathogenic (P/LP) genetic variants for HCM, and assess genetic testing yield and variant spectrum by self-identified ethnicity. Probands with HCM and enrolled in Cardiac Inherited Diseases Registry New Zealand who have undergone clinical genetic testing over a 17-year period were included. Clinical data, family history, and genetic test results were analyzed. Of 336 probands, 121 (36%) were women, 220 (66%) were European ethnicity, 41 (12%) were Māori, 26 (8%) were Pacific people, and 49 (15%) were other ethnicities. Thirteen probands (4%) presented with sudden death and 19 (6%) with cardiac arrest. A total of 134 (40%) had a P/LP variant identified; most commonly in the MYBPC3 gene (60%) followed by the MYH7 gene (24%). A P/LP variant was identified in 27% of Māori or Pacific probands versus 43% European or other ethnicity probands (P=0.022); 16% of Māori or Pacific probands had a variant of uncertain significance identified, compared with 9% of European or other ethnicity probands (P=0.092). Women more often had a P/LP variant identified than men (48% versus 35%; P=0.032), and variant-positive probands were younger at clinical diagnosis than variant of uncertain significance/variant-negative probands (39±17 versus 50±17 years; P<0.001) and more likely to have experienced cardiac arrest or sudden death events over their lifetime (P=0.002). Carriage of a P/LP variant in HCM probands is associated with presentation at younger age, and cardiac arrest or sudden death events. Māori or Pacific probands were less likely to have a P/LP variant identified than European or other ethnicity probands.

Un cuore grande così... dalla nascita

The diagnosis of dilatative cardiomyopathy due to a new mutation of MYH7 gene was eventually made in a 1-month-old infant presenting with dyspnoea and difficult feeding.

Diversity in genetic risk of recurrent stroke: a genome-wide association study meta-analysis

IntroductionStroke is a leading cause of death and disability worldwide. Recurrent strokes are seven times more lethal than initial ones, with 54% leading to long-term disability. Substantial recurrent stroke risk disparities exist among ancestral groups. Notably, Africans face double the risk and higher fatality rates compared to Europeans. Although genetic studies, particularly GWAS, hold promise for uncovering biological insights into recurrent stroke, they remain underexplored. Our study addresses this gap through meta-analyses of recurrent stroke GWAS, considering specific ancestral groups and a combined approach.MethodsWe utilized four independent study cohorts for African, European, and Combined ancestry recurrent stroke GWAS with genotyping, imputation, and strict quality control. We harmonized recurrent stroke phenotype and effect allele estimates across cohorts. The logistic regression GWAS model was adjusted for age, sex, and principal components. We assessed how well genetic risk of stroke informs recurrent stroke risk using Receiver Operating Characteristic (ROC) curve analysis with the GIGASTROKE Consortium's polygenic risk scores (PRS).ResultsHarmonization included 4,420 participants (818 African ancestry and 3,602 European ancestry) with a recurrent stroke rate of 16.8% [median age 66.9 (59.1, 73.6) years; 56.2% male]. We failed to find genome-wide significant variants (p &amp;lt; 5e−8). However, we found 18 distinct suggestive (p &amp;lt; 5e−6) genetic loci with high biological relevance consistent across African and European ancestries, including PPARGC1B, CCDC3, OPRL1, and MYH11 genes. These genes affect vascular stenosis through constriction and dilation. We also observed an association with SDK1 gene, which has been previous linked with hypertension in Nigerian and Japanese populations). ROC analysis showed poor performance of the ischemic stroke PRS in discriminating recurrent stroke status (area under the curve = 0.48).DiscussionOur study revealed genetic associations with recurrent stroke not previously associated with incident ischemic stroke. We found suggestive associations in genes previously linked with hypertension. We also determined that knowing the genetic risk of incident stroke does currently not inform recurrent stroke risk. We urgently need more studies to understand better the overlap or lack thereof between incident and recurrent stroke biology.

Variants of the promoter of MYH6 gene in congenital isolated and sporadic patent ductus arteriosus: case-control study and cellular functional analyses.

Patent ductus arteriosus (PDA) is a common form of congenital heart disease. The MYH6 gene has important effects on cardiovascular growth and development, but the effect of variants in the MYH6 gene promoter on ductus arteriosus is unknown. DNA was extracted from blood samples of 721 subjects (428 patients with isolated and sporadic PDA and 293 healthy controls) and analyzed by sequencing for MYH6 gene promoter region variants. Cellular function experiments with three cell lines (HEK-293, HL-1, and H9C2 cells) and bioinformatics analyses were performed to verify their effects on gene expression. In the MYH6 gene promoter, 11 variants were identified. Four variants were found only in patients with PDA and 2 of them (g.3434G>C and g.4524C>T) were novel. Electrophoretic mobility shift assay showed that the transcription factors bound by the promoter variants were significantly altered in comparison to the wild-type in all three cell lines. Dual luciferase reporter showed that all the 4 variants reduced the transcriptional activity of the MYH6 gene promoter (P < 0.05). Prediction of transcription factors bound by the variants indicated that these variants alter the transcription factor binding sites. These pathological alterations most likely affect the contraction of the smooth muscle of ductus arteriosus, leading to PDA. This study is the first to focus on variants at the promoter region of the MYH6 gene in PDA patients with cellular function tests. Therefore, this study provides new insights to understand the genetic basis and facilitates further studies on the mechanism of PDA formation.

A MYH7 variant in a five-generation-family with hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a genetic condition with a prevalence of 1:500-1:3 000. Variants in genes encoding sarcomeric proteins are mainly responsible for the disease. MYH7 gene encoding a myosin heavy chain beta, together with MYPBC3 gene are the two most commonly affected genes. The clinical presentation of this disease varies widely between individuals. This study aims to report a variant of MYH7 responsible for HCM in a five-generation family with a history of cardiac problems. Methods: The diagnosis was established according to the European Society of Cardiology HCM criteria based on two-dimensional Doppler echocardiography or cardiovascular magnetic resonance. Genetic analysis was performed using next-generation-sequencing and Sanger method. Results: The medical history of the presented family began with a prenatal diagnosis of HCM in the first child of a family with previously healthy parents. Five generations of the family had a long history of sudden cardiac death and cardiac problems. A NM_000257.4:c.2342T>A (p.Leu781Gln) variant was detected in the MYH7 gene. It was heterozygous in the proband and in all affected individuals in a large family. The variant was present in 10 affected members of the family, and was absent in 7 members. The clinical course of the disease was severe in several members of the family: three family members died of sudden cardiac death, one patient required heart transplantation, three underwent septal myectomy, and three required implantable cardioverter defibrillator (ICD) implantation. Conclusion: Herein, we report a MYH7 variant responsible for HCM. Familial HCM is inherited primarily in autosomal dominant mode, which is in accordance with our study. However, the presented family showed a broad clinical spectrum of HCM. Out of 10 family members with positive genetic testing 8 had severe presentation of the disease and 2 had a mild phenotype. This suggests that the severity of the disease may depend on other factors, most likely genetic.

Growth Hormone Receptor and PCSK9 Define a New Paradigm in the Initiation and Development of Chronic Kidney Disease as Revealed by Exome Sequencing on Illumina Platform

Chronic kidney disease is a combination of many vascular diseases involving mutations of many genes. Hypertension diabetes and atherosclerosis are the most common causes of kidney disease, with hypertension causing just over a quarter of all cases of kidney failure and diabetes causing one-third of them. Other much less common conditions that can cause CKD include inflammation, infections, genetic factors, or longstanding blockage to the urinary system (such as enlarged prostate or kidney stones). In many cases, the causes remained unknown, albeit the manifestation of the diseases with clear phenotypes and biochemical profiles. Heredity and genetic determinants play major roles in the initiation, development, and establishment of CKD. Kidney disease phenotypes can be dissected into many underlying causing candidates’ genes and many molecular genetics approaches are striving to lift the veil on this nagging disease. Recent studies using genetic testing have demonstrated that Mendelian etiologies account for approximately 20% of cases of kidney disease of unknown etiology. CKD is known to be plagued with many genes mutations like mutation in Autosomal Dominant Polycystic Kidney Disease (ADPKD) and mutations in MYH9 and APOL1 genes, COL4A3, COL4A4, and COL4A5 genes playing important roles in the CKD picture. Genetic testing has modernized and revolutionized many areas of medical practices and diagnosis of many diseases and the field of nephrology is not an exception. The advance in Next-generation Sequencing, including whole exome sequencing has proven to be a powerful tool in personalized medicine and for potential noninvasive decryption for biomarkers in kidney disease thereby paving the way for better diagnostic purposes. In this regard, we run whole exome sequencing on whole blood genomic DNA from CKD patients. Bioinformatics analysis led us to uncover a total of more than 3000 single nucleotide polymorphisms (SNPs). To sort out these flurries of targeted SNPs, we undertook filtration using an R-algorithm in combination with the diseases association Clinvar database. This approach led us to 12 combined diagnostic missense variants scattered on different chromosomes. Combined missense reduction after FDR filtration with a Cellrate of 0.75 generated two missense variants located on PCSK9 and GHR genes on chromosomes 1 and 5 and lastly, reduction variants after Filtration by spliced region bring us to a single SNP located on the PCSK9 gene.

Genetic predisposition to differentiated thyroid cancer in the Polish population.

Genome sequencing technologies reveal molecular mechanisms of differentiated thyroid cancer (DTC). Unlike somatic mutation analysis from thyroidectomy samples, germline mutations showing genetic susceptibility to DTC are less understood. The study aimed to assess the prevalence of germline mutations predisposing to DTC in a cohort of Polish individuals based on their whole genome sequencing data. We analyzed sequencing data from 1076 unrelated individuals totaling over 1018 billion read pairs and yielding an average 35.26 × read depth per genome, released openly for academic and clinical research as the Thousand Polish Genomes database (https://1000polishgenomes.com). The list of genes chosen for further analysis was based on the review of previous studies. The cohort contained 104 variants located within the coding and noncoding DNA sequences of 90 genes selected by ClinVar classification as pathogenic and potentially pathogenic. The frequency of variants in the Polish cohort was compared with the frequency estimated for the non‑Finnish European population obtained from the gnomAD database (gnomad.broadinstitute.org). Significant differences in variant frequency were found for the APC, ARSB, ATM, BRCA1, CHEK2, DICER1, GPD1L, INSR, KCNJ10, MYH9, PALB2, PLCB1, PLEKHG5, PTEN, RET, SEC23B, SERPINA1, SLC26A4, SMAD3, STK11, TERT, TOE1, and WRN genes. Even though the Polish population is genetically similar to the other European populations, there are significant differences in variant frequencies contributing to the disease development and progression, such as those in the RET, CHEK2, BRCA1, SLC26A4, or TERT genes. Further studies are needed to identify genomic variants associated directly with DTC.

Stable thyroid cancer in a patient with thoracic aortic aneurysm and MYH11 variation.

We report the case of a male patient with papillary thyroid cancer, familial thoracic aortic aneurysm and dissection, and a variation in the MYH11 gene. Because of considerable tumor bulk in the neck that was not resectable, the patient underwent partial resection at age 14 years. Since then, the patient has received only suppressive thyroid hormone therapy. He is now 71 years old, which is 57 years after the initial resection. The patient received care at our institution from July 2009 to August 2019, during which we documented the stability of multiple calcified masses in the neck. Follow-up examinations at another institution from September 2019 to April 2023 also confirmed the stability of the masses. The underlying cause of this unusually long indolent course of the disease is unclear. Whether extensive tumor calcifications or the MYH11 sequence variation contributed to the disease course is also uncertain. Papillary thyroid cancer with neck metastases may, in some cases, be stable and remain asymptomatic for decades. If locoregional stability of papillary thyroid cancer is documented for many years, observation may be preferable to extensive neck surgery in selected cases. This is the first report of an MYH11 gene alteration and thoracic aortic aneurysm in a patient with papillary thyroid cancer with indolent neck metastases. Future studies of MYH11 gene alterations in thyroid carcinoma are needed.

Clinical and genetic characterisation of hereditary distal myopathies in a series of Colombian patients

Hereditary distal myopathies represent a heterogeneous group of rare genetic disorders characterized by progressive distal muscle weakness. The objective of this study was to describe the clinical spectrum and genetic findings in a series of patients with distal myopathy from Colombia. A retrospective review of the medical records of 12 patients with distal myopathy seen at a neuromuscular center in Bogota, Colombia, between 2015 and 2023 was performed. Clinical data, family history, diagnostic studies and genetic test results were obtained. The mean age of onset was 15.7 years. Patterns of limb weakness included distal involvement in the upper and lower extremities (50%), distal involvement in the lower extremities in isolation (33.3%), and proximal and distal involvement in the upper and lower extremities (8.3%). Additional weakness was observed in the face (8.3%) and paraspinal muscles (25.0%). Creatine kinase levels were elevated in 58.3% of cases. Electromyography revealed a myopathic pattern in 91.6% of cases. Variants identified included MYH7, ANO5, TTN, HNRNPA1, DES, DYSF and CAV3 genes. This case series describes the clinical and genetic spectrum of inherited distal myopathies in Colombia. Findings demonstrate phenotypic and genotypic heterogeneity, with variants in genes encoding structural proteins. There is a need to expand access to genetic testing in Latin America to enable more accurate comprehensive diagnosis and treatment.

Association of polymorphisms in FBN1, MYH11, and TGF-β signaling-related genes with susceptibility of sporadic thoracic aortic aneurysm and dissection in the Zhejiang Han population.

Sporadic thoracic aortic aneurysm and dissection (sTAAD) is a complicated vascular disease with a high mortality rate. And its genetic basis has not been fully explored. Here, 122 sTAAD patients and 98 healthy individuals were recruited, and 10 single nucleotide polymorphisms were selected and analyzed (FBN1 rs10519177, rs1036477, rs2118181, MYH11 rs115364997, rs117593370, TGFβ1 rs1800469, TGFβ2 rs900, TGFβR2 rs764522, rs1036095, and rs6785385). Moreover, multiple logistic regression analysis was used to evaluate gene-environment interactions. We identified that TGFβR2 rs1036095 dominant model CC + CG genotype (GT) (P = 0.004) may be a factor of increased risk of sTAAD, especially for women. FBN1 rs1036477 recessive model AA GT (P = 0.009) and FBN1 rs2118181 dominant model CC + CT GT (P = 0.009) were correlated to an increased death rate in sTAAD men patients. Gene-environment interactions indicated TGFβR2 rs1036095 dominant model (CC + CG)/GG to be a higher-risk factor for sTAAD (odds ratio = 3.255; 95% confidence interval: 1.324-8.000, P = 0.01). TGFβR2 rs1036095, FBN1 rs1036477, and FBN1 rs2118181 were identified as factors of increased risk of sTAAD. Gene-environment interactions were associated with the risk of sTAAD.