Zusammenfassung
Die verbesserte Therapie und Prophylaxe von Herz-Kreislauf-Erkrankungen hat wie kein anderer Bereich der Medizin zum Anstieg der Lebenserwartung beigetragen. Dennoch bleiben viele ...kardiologische Krankheiten schlecht therapierbar, und Standardtherapien nutzen nur einer Minderheit von Patienten oder verursachen mehr Nebenwirkungen als Nutzen. Personalisierte Ansätze versprechen neue Lösungswege. Die seltenen monogenen Herz-Kreislauf-Erkrankungen sind hierfür paradigmatisch und lassen sich heute in Einzelfällen „mutationsspezifisch“ behandeln. Dennoch sind die Erfolge insgesamt noch bescheiden. Das „next generation sequencing“ wird die Identifizierung krankheitsverursachender Mutationen erleichtern. Zellkulturmodelle auf der Basis induzierter pluripotenter Stammzellen lassen eine individuelle Testung pharmakologischer oder gentherapeutischer Therapieansätze erwarten. Gegenwärtig noch von untergeordneter klinischer Bedeutung ist die genetische Testung bei multifaktoriellen kardiovaskulären Volkskrankheiten. Biomarker haben dagegen das Potenzial, Individuen mit erhöhtem kardiovaskulärem Risiko zu identifizieren. Individualisierte, biomarkergeführte Therapien stellen eine attraktive Option für die Zukunft dar. Dafür ist die troponingesteuerte Therapie akuter Koronarsyndrome erfolgreiches Beispiel. Schließlich ist die individuelle Reaktion auf Arzneimittel teilweise genetisch determiniert und lässt sich mithilfe genetischer Analysen besser vorhersagen. Praktische Beispiele in der kardiovaskulären Medizin sind Warfarin und hohe Dosen von Simvastatin. Zusammengefasst werden personalisierte Ansätze in der kardiovaskulären Medizin sicher zunehmen. Dies erfordert die Entwicklung robusterer Methoden und Forschungen, die den tatsächlichen praktischen Nutzen der neuen Erkenntnisse auf den Prüfstand stellen.
Genetische und klinische Heterogenität bei LCA-Patienten Preising, M.N.; Paunescu, K.; Friedburg, C. ...
Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft,
6/2007, Volume:
104, Issue:
6
Journal Article
Muskeldystrophien Neuen-Jacob, E.
Der Pathologe,
09/2009, Volume:
30, Issue:
5
Journal Article
Zusammenfassung
Die Diagnose „Muskeldystrophie“ ohne genauere Zuordnung des zugrunde liegenden Gendefekts ist heutzutage obsolet. Die Entdeckung und Klonierung zahlreicher Zytoskelettproteine und ...Intermediärfilamente an der Muskelfasermembran, im Sarkoplasma und im Muskelfaserkern, deren Zusammenspiel für die normale Funktion der Muskelfaser essenziell ist, hat die Klassifikation der Muskeldystrophien revolutioniert. Es handelt sich um eine klinisch und genetisch sehr heterogene Gruppe von Erkrankungen. Mit immunhistochemischen und molekulargenetischen Methoden können mehr als 40 Formen abgegrenzt werden, die durch bestimmte Proteindefekte bzw. definierte Genloci charakterisiert sind und denen bestimmte Phänotypen zugeordnet werden können. Es ist wichtig zu wissen, dass Muskeldystrophien mit einer Kardiomyopathie mit erhöhtem Risiko für einen plötzlichen Herztod assoziiert sein können. Die Diagnostik und Behandlung sollte daher erfahrenen Spezialisten vorbehalten bleiben, vorzugsweise in einem Muskelzentrum.
Early kidney failure in the hereditary type IV collagen disease, Alport syndrome, can be delayed by renin-angiotensin inhibitors. However, whether all patients and all different genotypes respond ...equally well to this kidney-protective therapy remains unclear. Here, we performed a retrospective study on 430 patients with male X-linked Alport syndrome to examine the relationships among kidney prognosis, genotype, and treatment effect in a large cohort of Japanese patients. We analyzed the clinical features, genotype-phenotype correlation, and kidney survival period for patients treated with or without renin-angiotensin inhibitors. As a result, the median kidney survival period of patients in this cohort was found to be at 35 years with a strong genotype-phenotype correlation. The median age at the onset of end stage kidney disease (ESKD) significantly differed between patients treated with and without renin-angiotensin inhibitors (over 50 years versus 28 years, respectively). Moreover, these drugs delayed the onset of ESKD in patients with truncating variants for 12 years, extending the median age from 16 years to 28 years. Thus, our results confirmed a strong genotype-phenotype correlation in patients with male X-linked Alport syndrome. Additionally, it was suggested that renin-angiotensin inhibitors could significantly delay ESKD progression. Despite these therapies, patients with truncating variants developed ESKD at the median age of 28 years.
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Non-syndromic retinitis pigmentosa Verbakel, Sanne K.; van Huet, Ramon A.C.; Boon, Camiel J.F. ...
Progress in retinal and eye research,
September 2018, 2018-09-00, 20180901, Volume:
66
Journal Article
Peer reviewed
Open access
Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, ...with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
•MFRP emerges as the predominant disease-causing gene in a large Chinese microphthalmia cohort.•Variant p.E496K exhibits the highest frequency among nine novel and seven known variants.•The ...association of p.E496K with a short axial length represents a novel genotype-phenotype correlation.
Microphthalmia is a severe congenital ocular disease featured by abnormal ocular development. The aim of this study was to detail the genetic and clinical characteristics of a large cohort of Chinese patients with microphthalmia related to MFRP variants, focusing on uncovering genotype-phenotype correlations.
Fifty microphthalmia patients from 44 unrelated Chinese families were recruited. Whole-exome sequencing (WES) was conducted to analyze the coding regions and adjacent intronic regions of MFRP. Axial lengths (AL) were measured for all probands and available family members. Protein structures of mutations with high frequency in our cohort were predicted. The genotype-phenotype correlations were explored by statistical analysis.
Sixteen MFRP variants were detected in 17 families, accounting for 38.64 % of all microphthalmia families. There were 9 novel mutations (c.427+1G>C, c.428-2A>C, c.561_575del:p.A188_E192del, c.836G>A:p.C279Y, c.1010_1021del:p.H337_E340del:p.Y479*, c.1516_1517del:p.S506Pfs*66, c.1561T>G:p.C521G, c.1616G>A:p.R539H, and c.1735C>T:p.P579S) and six previously reported variants in MFRP, with p.E496K and p.H337_E340del being highly frequent, found in eight (47.06 %) and two families (11.76 %), respectively. Seven variants (43.75 %) were located in the C-terminal cysteine-rich frizzled-related domain (CRD) (7/16, 43.75 %). Protein prediction implicated p.E496K and p.H337_E340del mutations might lead to a destabilization of the MFRP protein. The average AL of all 42 eyes was 16.02 ± 1.05 mm, and 78.36 % of eyes with AL < 16 mm harbored p.E496K variant. Twenty-six eyes with variant variant had shorter AL than that of the other 16 eyes without this variant (p = 0.006), highlighting a novel genotype-phenotype correlation.
In this largest cohort of Chinese patients with microphthalmia, the 9 novel variants, high frequency of p.E496W, and mutation hotspots in CRD reveals unique insights into the MFRP mutation spectrum among Chinese patients, indicating ethnic variability. A new genotype-phenotype correlation that p.E496K variant associated with a shorter AL is unveiled. Our findings enhance the current knowledge of MFRP-associated microphthalmia and provide valuable information for prenatal diagnosis as well as future therapy.
Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC ...pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index‐patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non‐compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease‐causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in‐frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non‐compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.
ABSTRACT
The 364 exon TTN gene encodes titin (TTN), the largest known protein, which plays key structural, developmental, mechanical, and regulatory roles in cardiac and skeletal muscles. Prior to ...next‐generation sequencing (NGS), routine analysis of the whole TTN gene was impossible due to its giant size and complexity. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. In the last months, due to the widespread use of NGS, TTN is emerging as a major gene in human‐inherited disease. So far, 127 TTN disease‐causing mutations have been reported in patients with at least 10 different conditions, including isolated cardiomyopathies, purely skeletal muscle phenotypes, or infantile diseases affecting both types of striated muscles. However, the identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance, and correlation with the phenotype of TTN sequence changes. In this review, we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern, and phenotype–genotype correlations, alongside with their implications for basic research and for human health.
The 364 exon TTN gene encodes the giant protein titin, a key player in cardiac and skeletal muscles. Lately, NGS is revealing TTN as a major gene in human inherited disease, with 127 TTN disease‐causing mutations reported in patients with at least 10 different conditions. Here we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern and phenotype‐genotype correlations, alongside with their implications for basic research and human health.
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