Responsible Gene Mutation Research Articles

Identification of antimicrobial resistance profiles and antimicrobial resistance genes of Campylobacter isolates from broiler farms in Sri Lanka

Antimicrobial resistant (AMR) bacteria including Campylobacter has become an emerging global concern in human and animal health. There are very few researches on AMR Campylobacter conducted in Sri Lanka and none of them studied about AMR genes to the best of our knowledge. The present study focused on the detection of AMR Campylobacter from broiler in Sri Lanka, resistant against frequently used antimicrobials. Further, presence of AMR genes or mutations in responsible genes were compared to the resistant phenotypes. Cloacal swabs were collected from 118 broilers in nine farms covering three provinces in Sri Lanka. One Campylobacter colony per sample was isolated and the antimicrobial susceptibility test of the isolates was performed by inoculating the isolates onto agar plates with threshold concentrations of eight antimicrobial agents which belong to six antimicrobial classes. Three genetic markers for antimicrobial resistance, point mutations in 23S rRNA gene and gyrA gene, and the presence of resistant gene, tet(O) were also investigated. Altogether, 73 samples were Campylobacter positive of which 59 were Campylobacter jejuni, 13 were Campylobacter coli and one was unidentified Campylobacter. All isolates were resistant to three or more antimicrobials tested. The isolates were frequently resistant to ciprofloxacin, nalidixic acid, trimethoprim-sulfamethoxazole, amoxicillin and tetracycline, and susceptible to gentamicin and streptomycin, while the resistance to erythromycin was different between the species. Genetic screening revealed that most of the isolates possessed one or more of these genetic markers. This study urges the need of continuous surveillance for AMR Campylobacter in Sri Lanka.

Characterization of a Novel Gja8 (Cx50) Mutation in a New Cataract Rat Model.

To describe a novel spontaneous cataract inbred strain isolated from large-scale breeding SD rats, identify the responsible gene mutation, and understand how this mutation affects lens function. Exome sequencing of 12 cataract-associated genes was performed in the affected and healthy relatives. Sequences of rat wild-type or mutant gap junction protein alpha 8 gene (Gja8) were transfected into cells. The expression level of protein was assayed by Western blot analysis. Subcellular localization of connexin 50 (Cx50) was analyzed in confocal fluorescent images. Wound-healing, 5-ethynyl-2'-deoxyuridine incorporation, and attachment assay were performed to characterize the cell migration, proliferation and adhesion. The abnormality was found to be inheritable in an autosomal semi-dominant pattern through different mating patterns. We found a G to T transversion at codon 655 in Gja8, leading to a substitution of valine by phenylalanine (p.V219F). Gja8V219F/+ heterozygotes expressed nuclear cataract while Gja8V219F/V219F homozygotes manifested microphthalmia in addition to cataract. Histology revealed fiber disorders and loss of organelle-free zone in the mutant lens. Cx50V219F altered its location in HeLa cells and inhibited the proliferation, migration and adhesion abilities of HLEB3 cells. The mutation also reduced the expression of focal adhesion kinase and its phosphorylation. The c.655G>T mutation (p.V219F) is a novel mutation in Gja8, inducing semi-dominant nuclear cataracts in a new spontaneous cataract rat model. The p.V219F mutation altered Cx50 distribution, inhibited lens epithelial cell proliferation, migration, and adhesion, and disrupted fiber cell differentiation. As a consequence, the nuclear cataract and small lens formed.

Gene mapping methodology powered by induced genome rearrangements

Phenotypic variation occurs through genome rearrangements and mutations in certain responsible genes; however, systematic gene identification methodologies based on genome rearrangements have not been fully established. Here, we explored the loci responsible for the given phenotype using the TAQing system and compared it with a conventional mutagenesis-based method. Two yeast strains with different genetic backgrounds and flocculation phenotypes were fused and genomic rearrangements were induced by transient DNA breaks. Then, selection pressure was applied and multiple mutants were generated, showing different flocculation abilities. We also raised mutants with altered cohesiveness due to spontaneous mutations during long-term recursive passages of haploid strains without TAQing treatment. Comparative genomic analysis of the TAQed mutants revealed three chromosomal regions harboring pivotal flocculation genes, whereas conventional mutagenesis generated a more diverse list of candidate loci after prolonged selection. The combined use of these approaches will accelerate the identification of genes involved in complex phenotypes.

A comprehensive interaction study provides a potential domain interaction network of human death domain superfamily proteins

Human death domain superfamily proteins (DDSPs) play important roles in many signaling pathways involved in cell death and inflammation. Disruption or constitutive activation of these DDSP interactions due to inherited gene mutations is closely related to immunodeficiency and/or autoinflammatory diseases; however, responsible gene mutations have not been found in phenotypical diagnosis of these diseases. In this study, we comprehensively investigated the interactions of death-fold domains to explore the signaling network mediated by human DDSPs. We obtained 116 domains of DDSPs and conducted a domain–domain interaction assay of 13,924 reactions in duplicate using amplified luminescent proximity homogeneous assay. The data were mostly consistent with previously reported interactions. We also found new possible interactions, including an interaction between the caspase recruitment domain (CARD) of CARD10 and the tandem CARD–CARD domain of NOD2, which was confirmed by reciprocal co-immunoprecipitation. This study enables prediction of the interaction network of human DDSPs, sheds light on pathogenic mechanisms, and will facilitate identification of drug targets for treatment of immunodeficiency and autoinflammatory diseases.

Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis - Protocol for a randomized, double-blind, placebo-controlled, single-center, and open-label continuation phase I/IIa clinical trial (ROPALS trial).

IntroductionAmyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial.MethodsThe ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years.ConclusionPatient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020.Trial registrationCurrent controlled trials UMIN000034954 and JMA-IIA00397Protocol versionversion 1.6 (Date; 5/Apr/2019).

Influence of Genetics and Gender in Takotsubo Syndrome: Unexplored Areas of an Incompletely Understood Disease

Stress cardiomyopathy, also known as “Takotsubo syndrome” (TS), is a complex disease that typically affects postmenopausal women. The pathophysiology is still largely unknown, but evidence of a frequent association between TS and stressful events has evoked the hypothesis of a pathophysiologic role of sympathetic overdrive in the myocardial dysfunction. However, despite several studies, the role gender plays in TS onset remains unclear because stress cardiomyopathy also has been described in young women and in men. Moreover, although several cases of a familial cluster of TS have been reported, no responsible gene mutations or polymorphisms have been clearly identified so far, and neither the modality of transmission or the true impact of genetic background. In this review, we discuss the role of gender in the onset, course, and outcomes of TS and we report the available data about polymorphisms and gene mutations so far investigated, trying to critically analyze the evidence reported in the literature.

HLA-A24 ligandome analysis of colon and lung cancer cells identifies a novel cancer-testis antigen and a neoantigen that elicits specific and strong CTL responses

ABSTRACTThis study focused on HLA-A24 and comprehensively analyzed the ligandome of colon and lung cancer cells without the use of MHC-binding in silico prediction algorithms. Affinity purification using the antibody specific to HLA-A24 followed by LC–MS/MS sequencing was used to detect peptides, which harbored the known characteristics of HLA-A24 peptides in terms of length and anchor motifs. Ligandome analysis demonstrated the natural presentation of two different types of novel tumor-associated antigens. The ligandome contained a peptide derived from SUV39H2, a gene found to be expressed in a variety of cancers but not in normal tissues (except for the testis). The SUV39H2 peptide is immunogenic and elicits cytotoxic CD8+ T-cell (CTL) responses against cancer cells and is thus a novel cancer-testis antigen. Moreover, we found that microsatellite instability (MSI)-colon cancer cells displayed a neoepitope with an amino-acid substitution, while microsatellite stable (MSS)-colon and lung cancer cells displayed its counterpart peptide without the substitution. Structure modeling of peptide-HLA-A24 complexes predicted that the mutated residue at P8 was accessible to T-cell receptors. The neoepitope readily elicited CTL responses, which discriminated it from its wild-type counterpart, and the CTLs exhibited considerably high cytotoxicity against MSS-colon cancer cells carrying the responsible gene mutation. The specific and strong CTL lysis observed in this study fosters our understanding of immune surveillance against neoantigens.

Three-dimensional Evaluation of the Fetal Brain

ABSTRACT Three-dimensional (3D) ultrasound is one of the most attractive modalities in the field of fetal ultrasound imaging. Combination of both transvaginal sonography and 3D ultrasound may be a great diagnostic tool for evaluation of 3D structure of fetal central nervous system (CNS). Recent advanced 3D ultrasound equipments have several useful functions, such as surface anatomy imaging; multiplanar imaging of the intracranial structure; tomographic ultrasound imaging of fetal brain in the any cutting section; bony structural imaging of the calvaria and vertebrae; thick slice imaging of the intracranial structure; simultaneous volume contrast imaging of the same section or vertical section of fetal brain structure; volume calculation of target organs, such as intracranial cavity, ventricle, choroid plexus, and intracranial lesions; and 3D sonoangiography of the brain circulation (3D power or color Doppler). Furthermore, recent advanced technologies, such as HDlive silhouette and HDlive flow are quite attractive modalities and they can be applied for neuroimaging. Up-to-date 3D technologies described in this study allow extending the detection of congenital brain maldevelopment, and it is beyond description that noninvasive direct viewing of the embryo/fetus by all-inclusive ultrasound technology is definitely the first modality in a field of fetal neurology and helps our goal of proper perinatal care and management, even in the era of molecular genetics and advanced sequencing of fetal deoxyribonucleic acid (DNA) in the maternal blood. As a future aspect, collaboration of both molecular genetics and 3D neuroimaging will reveal responsible gene mutation of neuronal migration disorder, and this fetal neuro-sono-genetics will be able to contribute to accurate diagnoses, proper management, possible genetic therapy, and prophylaxis. How to cite this article Pooh RK. Three-dimensional Evaluation of the Fetal Brain. Donald School J Ultrasound Obstet Gynecol 2017;11(4):268-275.

Phenotypic Heterogeneity in a DFNA20/26 family segregating a novel ACTG1 mutation.

BackgroundGenetic factors play an important role in hearing loss, contributing to approximately 60 % of cases of congenital hearing loss. Autosomal dominant deafness accounts for approximately 20 % of cases of hereditary hearing loss. Diseases with autosomal dominant inheritance often show pleiotropy, different degrees of penetrance, and variable expressivity.MethodsA three-generation Chinese family with autosomal dominant nonsyndromic hearing impairment (ADNSHI) was enrolled in this study. Audiometric data and blood samples were collected from the family. In total, 129 known human deafness genes were sequenced using next-generation sequencing (NGS) to identify the responsible gene mutation in the family. Whole Exome Sequencing (WES) was performed to exclude any other variant that cosegregated with the phenotype.ResultsThe age of onset of the affected family members was the second decade of life. The condition began with high-frequency hearing impairment in all family members excluding III:2. The novel ACTG1 c.638A > G (p.K213R) mutation was found in all affected family members and was not found in the unaffected family members. A heterozygous c.638A > G mutation in ACTG1 and homozygous c.109G > A (p.V37I) mutation in GJB2 were found in III:2, who was born with hearing loss. The WES result concurred with that of targeted sequencing of known deafness genes.ConclusionsThe novel mutation p.K213R in ACTG1 was found to be co-segregated with hearing loss and the genetic cause of ADNSHI in this family. A homozygous mutation associated with recessive inheritance only rarely co-acts with a dominant mutation to result in hearing loss in a dominant family. In such cases, the mutations in the two genes, as in ACTG1 and GJB2 in the present study, may result in a more severe phenotype. Targeted sequencing of known deafness genes is one of the best choices to identify the genetic cause in hereditary hearing loss families.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0333-1) contains supplementary material, which is available to authorized users.

Review of X-linked syndromes with arthrogryposis or early contractures-aid to diagnosis and pathway identification.

The following is a review of 50 X-linked syndromes and conditions associated with either arthrogryposis or other types of early contractures. These entities are categorized as those with known responsible gene mutations, those which are definitely X-linked, but the responsible gene has not been identified, and those suspected from family history to be X-linked. Several important ontology pathways for known disease genes have been identified and are discussed in relevance to clinical characteristics. Tables are included which help to identify distinguishing clinical features of each of the conditions.

DTI tractography of lissencephaly caused by TUBA1A mutation

Several genetic causes have been identified in lissencephaly, including mutations in LIS1, DCX, ARX, RELN, VLDLR, WDR62, and TUBA1A genes. One may sometimes suggest the most likely gene mutation upon MRI findings when some specific features are seen, although image findings overlap among the causative gene mutations. A 1-year-old boy presented with intractable epilepsy, developmental delay and microcephalus. Brain MRI revealed lissencephaly with severe dysplasia of the cerebellum and brainstem. Diffusion tensor imaging (DTI) visualized radially aligned structures within the cortex, which is not observed in normal brain after birth (Fig. 1). Combination of severe posterior fossa abnormalities with lissencephaly suggested TUBA1A as the most likely responsible gene mutation. Mutation analysis of TUBA1A gene revealed a missense mutation of c.1205G>A, which was negative in both parents indicating a de novo mutation. Fig. 1 T1-weighted axial image (a) and T2-weighted axial images (b) show diffuse thickening of the cortex with lack of sulcation, accompanied by severe dysplasia of the brainstem and cerebellum. Obscuration of the contour of the basal ganglia and internal capsule ... Mutation of TUBA1A gene, coding for alpha I tubulin that constitutes subunit of microtubule, is a relatively rare cause of lissencephaly. The most consistent feature of lissencephaly due to TUBA1A mutation is severe cerebellar and brainstem abnormalities. Other characteristics include dysmorphic basal ganglia with hypoplastic internal capsule, callosal hypoplasia, and microcephaly, as seen in this case [1, 2]. Recently, mutations in the neuronally expressed tubulin genes have been reported to cause a spectrum of overlapping cortical malformations ranging from lissencephaly to polymicrogyria, and categorized as “tubulinopathy” [3]. Although cerebellar abnormalities may be present in LIS1 and DCX mutation, they are much less severe than in TUBA1A mutation. The radially aligned structure within the cortex and increase of cortical fractional anisotropy (FA) are transiently observed in the normal developing brain around 15–28 gestational weeks [4]. Normally, the cortical FA declines with development and approaches zero by 36 weeks [5]. This transient radially aligned anisotropic structure has been presumed to represent the presence of radial glia [4, 6]. The radial glias retract their ventricular and pial attachments and differentiate into astrocytes as the brain matures normally, with corresponding decrease in the cortical FA value. The radially oriented structure within the cortex demonstrated in this case may represent remains of radial glia or persistent radial orientation of neurons arrested in the migration process [7].

Gain‐of‐Function KCNH2 Mutations in Patients with Brugada Syndrome

Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST segment elevation on electrocardiograms (ECGs) that predisposes patients to sudden cardiac death as a result of polymorphic ventricular tachyarrhythmia or ventricular fibrillation (VF). In BrS patients, except for SCN5A, mutations in other responsible genes are poorly elucidated. We identified 4 KCNH2 mutations, T152I, R164C, W927G, and R1135H, in 236 consecutive probands with BrS or Brugada-like ECG. Three of these mutation carriers showed QTc intervals shorter than 360 milliseconds and 1 experienced VF. We performed patch-clamp analyses on I(Kr) reconstituted with the KCNH2 mutations in Chinese hamster ovary cells and compared the phenotypes of the patients with different genotypes. Three mutations, R164C, W927G, and R1135H, increased I(Kr) densities. Three mutations, T152I, R164C, and W927G, caused a negative shift in voltage-dependent activation curves. Only the R1135H mutant channel prolonged the deactivation time constants. We also identified 20 SCN5A and 5 CACNA1C mutation carriers in our cohort. Comparison of probands' phenotypes with 3 different genotypes revealed that KCNH2 mutation carriers showed shorter QTc intervals and SCN5A mutation carriers had longer QRS durations. All KCNH2 mutations that we identified in probands with BrS exerted gain-of-function effects on I(Kr) channels, which may partially explain the ECG findings in our patients.

Novel compound heterozygous mutations of POLR3A revealed by whole-exome sequencing in a patient with hypomyelination

ObjectiveCongenital white matter disorders are a heterogeneous group of hypomyelination disorders affecting the white matter of the brain. Recently, mutations in the genes encoding the subunits of RNA polymerase III (Pol III), POLR3A and POLR3B, have been identified as new genetic causes for hypomyelinating disorders. MethodWhole-exome sequencing was applied to identify responsible gene mutations in a 29-year-old female patient showing hypomyelination of unknown cause. To investigate the pathological mechanism underlying the hypomyelination in this patient, the expression level of 7SL RNA, a transcriptional target of Pol III, was analyzed in cultured skin fibroblasts derived from the patient with POLR3A mutations. ResultsNovel compound heterozygous mutations of POLR3A were identified in the patient, who started to show cerebellar signs at 3years, lost ambulation at 7years, and became bedridden at 18years. Brain magnetic resonance imaging showed severe volume loss in the brainstem, the cerebellum, and the white matter associated with hypomyelination. In addition to hypodontia and hypogonadism, she showed many pituitary hormone-related deficiencies. The expression level of 7SL RNA in cultured skin fibroblasts derived from this patient showed no significant abnormality. ConclusionThe many pituitary hormone-related deficiencies identified in this patient may be an essential finding for the Pol III-related leukodystrophies spectrum. Further investigation is needed for a better understanding of the disease mechanism.

Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes.

BackgroundSenescence-accelerated mice (SAM) are a series of mouse strains originally derived from unexpected crosses between AKR/J and unknown mice, from which phenotypically distinct senescence-prone (SAMP) and -resistant (SAMR) inbred strains were subsequently established. Although SAMP strains have been widely used for aging research focusing on their short life spans and various age-related phenotypes, such as immune dysfunction, osteoporosis, and brain atrophy, the responsible gene mutations have not yet been fully elucidated.ResultsTo identify mutations specific to SAMP strains, we performed whole exome sequencing of 6 SAMP and 3 SAMR strains. This analysis revealed 32,019 to 38,925 single-nucleotide variants in the coding region of each SAM strain. We detected Ogg1 p.R304W and Mbd4 p.D129N deleterious mutations in all 6 of the SAMP strains but not in the SAMR or AKR/J strains. Moreover, we extracted 31 SAMP-specific novel deleterious mutations. In all SAMP strains except SAMP8, we detected a p.R473W missense mutation in the Ldb3 gene, which has been associated with myofibrillar myopathy. In 3 SAMP strains (SAMP3, SAMP10, and SAMP11), we identified a p.R167C missense mutation in the Prx gene, in which mutations causing hereditary motor and sensory neuropathy (Dejerine-Sottas syndrome) have been identified. In SAMP6 we detected a p.S540fs frame-shift mutation in the Il4ra gene, a mutation potentially causative of ulcerative colitis and osteoporosis.ConclusionsOur data indicate that different combinations of mutations in disease-causing genes may be responsible for the various phenotypes of SAMP strains.

Pathogenesis of ectodermal dysplasia

Ectodermal dysplasias (ED) are characterized by impaired development of organs forming from the embryonic surface ectoderm. Thus, in ED organs like teeth, hair, nails and exocrine glands are hypoplastic or totally missing. The pathogenesis of the defects is starting to be understood thanks to the identification of the responsible gene mutations, and to the advances in developmental biology. Rapid progress particularly in genetics and in the generation of genetically modified animals such as transgenic mice has allowed the exploration of events leading to ectodermal organ defects at the cellular and molecular levels. Mouse models have been produced for many different ED syndromes. Most work so far has focused on hypohidrotic ED which is caused by mutations affecting the ectodysplasin (Eda) signalling pathway. Analyses of mouse mutants in which Eda signalling is either blocked (like in most patients with hypohidrotic ED) or overactivated have indicated that Eda signalling is a key regulator of ectodermal placodes. The placodes initiate the formation of ectodermal organs, their positions determine the location of these organs, and their size is associated with organ size. Eda signalling also affects later stages of development, influencing for instance the shape of teeth and branching of salivary and mammary glands. Recent data indicate that Eda signalling is intimately linked to many other signalling pathways, e.g. Wnt, BMP, and FGF pathways, which regulate cell communication together with Eda. The detailed understanding of the functions of these molecular networks can be expected to lead to new possibilities to prevent and treat ED.

Disease-dependent Differently Methylated Regions (D-DMRs) of DNA are Enriched on the X Chromosome in Uterine Leiomyoma

Uterine leiomyoma is the most common benign tumor in women. Although responsible gene mutations have not been found in leiomyomas, they represent a progressive disease with irreversible symptoms. To characterize epigenetic features of uterine leiomyomas, the DNA methylation status of a paired sample of leiomyoma and normal myometrium was subjected to a microarray-based DNA methylation analysis with restriction tag-mediated amplification (D-REAM). In the leiomyoma, we identified an aberrant DNA methylation status for 463 hypomethylated and 318 hypermethylated genes. Although these changes occurred on all chromosomes, aberrantly hypomethylated genes were preferentially located on the X chromosome. Using paired samples of normal myometrium and leiomyoma from 6 hysterectomy patients, methylation-sensitive quantitative real-time PCR revealed 14 shared X chromosome genes with an abnormal DNA hypomethylation status (FAM9A, CPXCR1, CXORF45, TAF1, NXF5, VBP1, GABRE, DDX53, FHL1, BRCC3, DMD, GJB1, AP1S2 and PCDH11X) and one hypermethylated locus (HDAC8). Expression of XIST, which is involved in X chromosome inactivation, was equivalent in the normal myometrium and leiomyoma, indicating that the epigenetic abnormality on the X chromosome did not result from aberration of XIST gene expression. Based on these data, a unique epigenetic signature for uterine leiomyomas has emerged. The 14 hypomethylated and one hypermethylated loci provide valuable biomarkers for understanding the molecular pathogenesis of leiomyoma.

Use of Genetics in the Clinical Evaluation and Management of Heart Failure

Inherited forms of cardiomyopathy are common causes of heart failure. Applications of genetics in the evaluation and management of heart failure include the determination of inheritance patterns within families with cardiomyopathy, the evaluation of affected patients for syndromic features, the determination of people within families who are at risk of heart failure, and the identification of responsible gene mutations. Family planning may also be assisted by determination of a clear mutation that predisposes to heart failure. Genetic counseling is critical, and it should accompany the use of genetic testing in cardiovascular diseases. With the rapid pace of growth in technology that is used to determine DNA sequence, costs have declined and clinical application of genetic testing has expanded. This is particularly relevant for heart failure, because each of the familial forms of cardiomyopathy may be caused by a mutation in many different genes. Most families share a unique gene mutation, and appropriate interpretation of novel DNA variants is essential for proper use. The evaluation of risk of arrhythmia in familial forms of heart failure may benefit from genetic testing, as mutations in the genes encoding lamin A/C, desmin, and cardiac troponin T are associated with increased risk of sudden cardiac death. Because of its complexity and the rapid rate of change in available genetic testing options, the genetic evaluation of heart failure is best suited to tertiary referral centers with specific expertise in this area.

Use of Genetics in the Clinical Evaluation of Cardiomyopathy

Inherited forms of cardiomyopathy are frequently responsible for heart failure that is otherwise unexplained. Evaluation of familial cardiomyopathy should include not only the individual patient, but also the pattern of inheritance within the family and assessment for the presence of syndromic features. The last 10 years have seen remarkable advances in genetics. Improvements in technology have lowered costs, such that clinical use of genetic testing is rapidly expanding. Genetic counseling about the potential risks and benefits of such testing is an important part of the care of individuals and families with inherited heart disease. Among inherited types of cardiomyopathy, the likelihood of finding a responsible gene mutation varies. Both hypertrophic and right ventricular forms of cardiomyopathy have a relatively high likelihood of finding a responsible gene mutation when testing is properly applied. Because of prominent genetic heterogeneity in familial dilated cardiomyopathy, recognition of pathogenic mutations is more challenging. With or without genetic testing, screening of family members who are at risk for an inherited form of cardiomyopathy leads to earlier identification, earlier treatment, and improved outcomes.

New fibrillin gene mutation - possible cause of ascending aortic dilation in patients with aortic valve disease: Preliminary results

Approximately 10% of patients who undergo surgery for aortic valve disease (stenosis or regurgitation) suffer from ascending aortic dilation (AAD). A possible genetic etiology of AAD associated with aortic valve disease has been repeatedly mentioned in the literature, but a specific responsible gene mutation has not been described. In the present study, two groups of patients were compared, all of whom underwent surgery for aortic valve disease. Group A was a cohort of 27 patients who suffered from aortic valve disease associated with AAD. Group B was a cohort of 29 patients with structural aortic valve disease, but without concomitant AAD (control group). Genomic DNA was extracted from the white blood cells of peripheral blood samples and was amplified using primers specific for chosen exons of the fibrillin-1 gene, including their intron/exon boundaries. Exons 26 and 27 were selected for analysis. Analysis of the intronic part situated close to exon 27 showed insertion of cytosine between nucleotide 37 682 and 37 683 of query sequence. This insertions was classified as IVS 37 682 and 37 683insC. This mutation was found in all 27 patients from group A (patients with structural aortic valve disease accompanied by significant AAD). The abovementioned mutation was not found in any of the 29 patients from group B. This finding has potential implications for risk stratification and therapeutic targeting not only for patients with existing disease, but also for the general population. Future studies are needed to determine the clinical utility of the finding; however, the present hypothesis needs to be verified by further molecular studies.

Congenital Duplication of the Palm Syndrome: Gene Analysis and the Molecular Basis of its Clinical Features

Congenital duplication of the palm is a rare syndrome with the following features: the dorsal aspects of both hands have thick palmar skin with no hair or nails; bilateral ulnar ray deficiency; short hypoplastic upper limbs; and severe lower limb abnormalities. In this paper, we report a new case of congenital duplication of the palm syndrome, provide its gene analysis identifying the responsible gene mutation in exon 4 of the WNT7a gene, and detail the molecular basis of its clinical features.