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Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children's growth. Up to 552 genes, including fibroblast growth factor receptor 3 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the FGFR3 gene: c.1138G>A and c.1138G>C in achondroplasia and c.1620C>A and c.1620C>G in hypochondroplasia. However, in some cases, the diagnostic investigations undertaken thus far have failed to identify the causal anomaly, which strengthens the relevance of the diagnostic strategies being further refined. We observed a Caucasian adult with clinical and radiographic features of achondroplasia, with no common pathogenic variant. Exome sequencing detected an FGFR3(NM_000142.4):c.1075+95C>G heterozygous intronic variation. In vitro studies showed that this variant results in the aberrant exonization of a 90-nucleotide 5' segment of intron 8, resulting in the substitution of the alanine (Ala359) for a glycine (Gly) and the in-frame insertion of 30 amino acids. This change may alter FGFR3's function. Our report provides the first clinical description of an adult carrying this variant, which completes the phenotype description previously provided in children and confirms the recurrence, the autosomal-dominant pathogenicity, and the diagnostic relevance of this FGFR3 intronic variant. We support its inclusion in routinely used diagnostic tests for osteochondrodysplasia. This may increase the detection rate of causal variants and therefore could have a positive impact on patient management. Finally, FGFR3 alteration via non-coding sequence exonization should be considered a recurrent disease mechanism to be taken into account for new drug design and clinical trial strategies.
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Acondroplasia , Osteocondrodisplasias , Niño , Adulto , Humanos , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Acondroplasia/diagnóstico , Acondroplasia/genética , Acondroplasia/patología , Mutación , Exones , Fenotipo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
Biallelic disease-causing variants in the ALPK3 gene were first identified in children presenting with a severe cardiomyopathy. More recently, it was shown that carriers of heterozygous ALPK3 null variants are at risk of developing hypertrophic cardiomyopathy (HCM) with an adult onset. Since the number of reported ALPK3 patients is small, the mutational spectrum and clinical data are not fully described. In this multi-centric study, we described the molecular and clinical spectrum of a large cohort of ALPK3 patients. Genetic testing using targeted next generation sequencing was performed in 16 183 cardiomyopathy index cases. Thirty-six patients carried at least one null ALPK3 variant. The five paediatric patients carried two ALPK3 variants, all presented an HCM phenotype with severe outcomes (one transplantation, one heart failure and one cardiac arrest). The 31 adult patients carried heterozygous variants and the main phenotype was HCM (n = 26/31); including 15% (n = 4) presented with an apical or a concentric form of hypertrophy. Reporting a large cohort of ALPK3 patients, this collaborative work confirmed a strong association with HCM and suggesting his screening in the context of idiopathic HCM.
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Cardiomiopatía Hipertrófica , Proteínas Musculares , Fenotipo , Proteínas Quinasas , Humanos , Cardiomiopatía Hipertrófica/genética , Masculino , Femenino , Adulto , Niño , Adolescente , Francia/epidemiología , Persona de Mediana Edad , Prevalencia , Mutación , Preescolar , Predisposición Genética a la Enfermedad , Estudios de Cohortes , Heterocigoto , Adulto Joven , Pruebas Genéticas , Lactante , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , AncianoRESUMEN
BACKGROUND: Among KCNH2 missense loss of function (LOF) variants, homozygosity -at any position in the Kv11.1/hERG channel - is very rare and generally leads to intrauterine death, while heterozygous variants in the pore are responsible for severe Type 2 long-QT syndrome (LQTS). We report a novel homozygous p.Gly603Ser missense variant in the pore of Kv11.1/hERG (KCNH2 c.1807G > A) discovered in the context of a severe LQTS. METHODS: We carried out a phenotypic family study combined with a functional analysis of mutated and wild-type (WT) Kv11.1 by two-electrode voltage-clamp using the Xenopus laevis oocyte heterologous expression system. RESULTS: The variant resulted in a severe LQTS phenotype (very prolonged corrected QT interval, T-wave alternans, multiple Torsades de pointes) with a delayed clinical expression in later childhood in the homozygous state, and in a Type 2 LQTS phenotype in the heterozygous state. Expression of KCNH2 p.Gly603Ser cRNA alone elicited detectable current in Xenopus oocytes. Inactivation kinetics and voltage dependence of activation were not significantly affected by the variant. The macroscopic slope conductance of the variant was three-fold less compared to the WT (18.5 ± 9.01 vs 54.7 ± 17.2 µS, p < 0.001). CONCLUSIONS: We characterized the novel p.Gly603Ser KCNH2 missense LOF variant in the pore region of Kv11.1/hERG leading to a severe but viable LQTS in the homozygous state and an attenuated Type 2 LQTS in heterozygous carriers. To our knowledge we provide the first description of a homozygous variant in the pore-forming region of Kv11.1 with a functional impact but a delayed clinical expression.
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Canal de Potasio ERG1 , Síndrome de QT Prolongado , Niño , Humanos , Canal de Potasio ERG1/genética , Síndrome de QT Prolongado/genética , Mutación Missense , Fenotipo , LinajeRESUMEN
BACKGROUND: Few clinical data are available on NEXN mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants. METHODS: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected. RESULTS: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events. CONCLUSIONS: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.
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Cardiomiopatías , Cardiomiopatía Dilatada , Cardiomiopatía Hipertrófica , Muerte Súbita del Lactante , Fibrilación Ventricular , Masculino , Lactante , Humanos , Adulto , Persona de Mediana Edad , Cardiomiopatía Dilatada/genética , Prevalencia , Cardiomiopatías/diagnóstico , Fenotipo , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/complicaciones , Muerte Súbita Cardíaca/etiología , Pronóstico , Proteínas de Microfilamentos/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders associated with significant morbidity and mortality for which substantial evidence for a genetic contribution was previously reported. We present a detailed molecular investigation of a cohort of 231 patients presenting with primary cardiomyopathy below the age of 18 years. METHODS: Cases with pediatric cardiomyopathies were analyzed using a next-generation sequencing (NGS) workflow based on a virtual panel including 57 cardiomyopathy-related genes. RESULTS: This molecular approach led to the identification of 69 cases (29.9% of the cohort) genotyped as a carrier of at least one pathogenic or likely pathogenic variant. Fourteen patients were carriers of two mutated alleles (homozygous or compound heterozygous) on the same cardiomyopathy-related gene, explaining the severe clinical disease with early-onset cardiomyopathy. Homozygous TNNI3 pathogenic variants were detected for five unrelated neonates (2.2% of the cohort), with four of them carrying the same truncating variant, i.e. p.Arg69Alafs*8. CONCLUSIONS: Our study confirmed the importance of genetic testing in pediatric cardiomyopathies. Discovery of novel pathogenic variations is crucial for clinical management of affected families, as a positive genetic result might be used by a prospective parent for prenatal genetic testing or in the process of pre-implantation genetic diagnosis.
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Cardiomiopatías , Secuenciación de Nucleótidos de Alto Rendimiento , Adolescente , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Niño , Pruebas Genéticas , Humanos , Recién Nacido , Mutación , Estudios ProspectivosRESUMEN
BACKGROUND: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. OBJECTIVES: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human. METHODS: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24th 2022. RESULTS: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients. CONCLUSIONS: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).
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Endodesoxirribonucleasas , Enfermedades Inflamatorias del Intestino , Interferón Tipo I , Lupus Eritematoso Sistémico , Nefritis Lúpica , Vasculitis , Anticuerpos Anticitoplasma de Neutrófilos/genética , Cromatina , ADN , Endodesoxirribonucleasas/genética , Endodesoxirribonucleasas/metabolismo , Humanos , Interferón Tipo I/genética , Interferones , Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/genética , Fenotipo , Vasculitis/diagnósticoRESUMEN
Hypobetalipoproteinemia is characterized by LDL-cholesterol and apolipoprotein B (apoB) plasma levels below the fifth percentile for age and sex. Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Nevertheless, many families with a FHBL phenotype carry APOB missense variants of uncertain significance (VUS). We here aimed to develop a proof-of-principle experiment to assess the pathogenicity of VUS using the genome editing of human liver cells. We identified a novel heterozygous APOB-VUS (p.Leu351Arg), in a FHBL family. We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in Huh7 cells using CRISPR-Cas9 technology and studied the APOB expression, synthesis and secretion by digital droplet PCR and ELISA quantification. The APOB expression was decreased by 70% in the heterozygous APOB-KO cells and almost abolished in the homozygous-KO cells, with a consistent decrease in apoB production and secretion. The APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant. Thus, the p.Leu351Arg affected the apoB secretion, which led us to classify this new variant as likely pathogenic and to set up a hepatic follow-up in this family. Therefore, the functional assessment of APOB-missense variants, using gene-editing technologies, will lead to improvements in the molecular diagnosis of FHBL and the personalized follow-up of these patients.
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Hígado Graso , Hipobetalipoproteinemia Familiar por Apolipoproteína B , Hipobetalipoproteinemias , Apolipoproteínas B/metabolismo , Sistemas CRISPR-Cas , Hígado Graso/genética , Humanos , Hipobetalipoproteinemia Familiar por Apolipoproteína B/genética , Hipobetalipoproteinemias/diagnóstico , Hipobetalipoproteinemias/genética , Hipobetalipoproteinemias/metabolismoRESUMEN
Andersen-Tawil Syndrome (ATS) is a rare disease defined by the association of cardiac arrhythmias, periodic paralysis and dysmorphic features, and is caused by KCNJ2 loss-of-function mutations. However, when extracardiac symptoms are atypical or absent, the patient can be diagnosed with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a rare arrhythmia at high risk of sudden death, mostly due to RYR2 mutations. The identification of KCNJ2 variants in CPVT suspicion is very rare but important because beta blockers, the cornerstone of CPVT therapy, could be less efficient. We report here the cases of two patients addressed for CPVT-like phenotypes. Genetic investigations led to the identification of p. Arg82Trp and p. Pro186Gln de novo variants in the KCNJ2 gene. Functional studies showed that both variants forms of Kir2.1 monomers act as dominant negative and drastically reduced the activity of the tetrameric channel. We characterize here a new pathogenic variant (p.Pro186Gln) of KCNJ2 gene and highlight the interest of accurate cardiologic evaluation and of attention to extracardiac signs to distinguish CPVT from atypical ATS, and guide therapeutic decisions. We also confirm that the KCNJ2 gene must be investigated during CPVT molecular analysis.
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PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.
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Cardiomiopatías , Muerte Súbita Cardíaca , Adolescente , Alelos , Cardiomiopatías/genética , Preescolar , Muerte Súbita Cardíaca/etiología , Humanos , Pirofosfatasa Inorgánica/genética , Pirofosfatasa Inorgánica/metabolismo , Proteínas Mitocondriales/genética , MutaciónRESUMEN
BACKGROUND AND OBJECTIVE: Molecular diagnosis in inherited cardiac diseases is challenging because of the significant genetic and clinical heterogeneity. We present a detailed molecular investigation of a cohort of 4185 patients with referrals for inherited cardiac diseases. METHODS: Patients suffering from cardiomyopathies (3235 probands), arrhythmia syndromes (760 probands), or unexplained sudden cardiac arrest (190 cases) were analyzed using a next-generation sequencing (NGS) workflow based on a panel of 105 genes involved in sudden cardiac death. RESULTS: (Likely) pathogenic variations were identified for approximately 30% of the cohort. Pathogenic copy number variations (CNVs) were detected in approximately 3.1% of patients for whom a (likely) pathogenic variation were identified. A (likely) pathogenic variation was also detected for 21.1% of patients who died from sudden cardiac death. Unexpected variants, including incidental findings, were present for 28 cases. Pathogenic variations were mainly observed in genes with definitive evidence of disease causation. CONCLUSIONS: Our study, which comprises over than 4000 probands, is one of most important cohorts reported in inherited cardiac diseases. The global mutation detection rate would be significantly increased by determining the putative pathogenicity of the large number of variants of uncertain significance. Identification of "unexpected" variants also showed the clinical utility of genetic testing in inherited cardiac diseases as they can redirect clinical management and medical resources toward a meaningful precision medicine. In cases with negative result, a WGS approach could be considered, but would probably have a limited impact on mutation detection rate as (likely) pathogenic variations were essentially clustered in genes with strong evidence of disease causation.
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Arritmias Cardíacas/diagnóstico , Cardiomiopatías/diagnóstico , Análisis de Secuencia de ADN/métodos , Arritmias Cardíacas/genética , Cardiomiopatías/genética , Variaciones en el Número de Copia de ADN , Muerte Súbita Cardíaca , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Patología MolecularRESUMEN
BACKGROUND: Severe ventricular rhythm disturbances are the hallmark of arrhythmogenic cardiomyopathy (ACM), and are often explained by structural conduction abnormalities. However, comprehensive investigations of ACM cell electrical instability are lacking. This study aimed to elucidate early electrical myogenic signature of ACM. METHODS: We investigated a 41-year-old ACM patient with a missense mutation (c.394C>T) in the DSC2 gene, which encodes desmocollin 2. Pathogenicity of this variant was confirmed using a zebrafish DSC2 model system. Control and DSC2 patient-derived pluripotent stem cells were reprogrammed and differentiated into cardiomyocytes (hiPSC-CM) to examine the specific electromechanical phenotype and its modulation by antiarrhythmic drugs (AADs). Samples of the patient's heart and hiPSC-CM were examined to identify molecular and cellular alterations. RESULTS: A shortened action potential duration was associated with reduced Ca2+ current density and increased K+ current density. This finding led to the elucidation of previously unknown abnormal repolarization dynamics in ACM patients. Moreover, the Ca2+ mobilised during transients was decreased, and the Ca2+ sparks frequency was increased. AAD testing revealed the following: (1) flecainide normalised Ca2+ transients and significantly decreased Ca2+ spark occurrence and (2) sotalol significantly lengthened the action potential and normalised the cells' contractile properties. CONCLUSIONS: Thorough analysis of hiPSC-CM derived from the DSC2 patient revealed abnormal repolarization dynamics, prompting the discovery of a short QT interval in some ACM patients. Overall, these results confirm a myogenic origin of ACM electrical instability and provide a rationale for prescribing class 1 and 3 AADs in ACM patients with increased ventricular repolarization reserve.
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Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/genética , Desmocolinas/genética , Electrocardiografía/métodos , Canales Iónicos/genética , Adulto , Animales , Arritmias Cardíacas/fisiopatología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Mutación Missense/genética , Pez CebraRESUMEN
Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and one of the most common causes of heart failure. TTN-truncating variants represent the most common cause of DCM. Similarly, among other prevalent DCM-causing genes, truncating variants were also frequently detected in BAG3, DSP, FLNC, and LMNA. For these four genes, the current study aims to determine the prevalence of deep intronic pathogenic variants that could lead to splice defects. A next-generation sequencing (NGS) workflow based on whole gene sequencing of BAG3, DSP, FLNC, and LMNA of a cohort of 95 DCM patients, for whom no putatively causative point mutations were identified after NGS of a panel of 48 cardiomyopathy-causing genes, was thus performed. Our approach did not lead us to reconsider the molecular diagnosis of any patient of the cohort. This study suggests that deep splice mutations do not account for a significant proportion of DCM cases. In contrast with MYBPC3 in hypertrophic cardiomyopathy cases, NGS of BAG3, DSP, FLNC, and LMNA whole intronic sequences would not significantly improve the efficiency of molecular diagnosis of DCM probands.
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Cardiomiopatía Dilatada/genética , Predisposición Genética a la Enfermedad , Proteínas Musculares/genética , Mutación Puntual , Adulto , Cardiomiopatía Dilatada/diagnóstico , Femenino , Células HeLa , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Patología MolecularRESUMEN
BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis. A common variant, the G allele in position c.1420 (c.1420G), has been associated with a decrease of both plasma PCSK9 and LDL-cholesterol concentrations. However, the functional effect of this variant is currently not well understood. We hypothesized that it could be explained by functional variants in linkage disequilibrium (LD), more specifically, by variants located in the PCSK9 3' UTR as targets for miR regulation of PCSK9 expression. METHODS: Variations in LD with c.1420G were studied in 1029 patients followed for dyslipidaemia. In silico studies identified potential miRNA binding sites induced by PCSK9 3'UTR variants in LD with c.1420G. Their functionality was studied with a luciferase reporter assay in HuH-7 cells and confirmed by cotransfection of anti-miRNAs. RESULTS: The c.*571C and c.*234T variants located in the PCSK9 3'UTR were found in tight LD with c.1420G (D' = 0.962; LOD = 163.06). The haplotype carrying c.*571C showed a 6.7% decrease in luciferase activity (p = 0.003). Inhibition of hsa-miR-1228-3p and hsa-miR-143-5p counteracted their effect on the haplotype carrying c.*571C allele, suggesting that PCSK9 expression was decreased by the endogenous binding of hsa-miR-1228-3p and hsa-miR-143-5p on its 3'UTR. CONCLUSIONS: This post-transcriptional regulation might contribute towards the association between plasma PCSK9 levels and c.1420G. Such regulation of PCSK9 expression may open new perspectives for the treatment of hypercholesterolemia and atherosclerosis cardiovascular diseases.
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MicroARNs , Proproteína Convertasa 9 , Regiones no Traducidas 3' , Sitios de Unión , Humanos , Desequilibrio de Ligamiento , MicroARNs/genética , Proproteína Convertasa 9/genéticaRESUMEN
The aim of this study was to provide an efficient tool: reliable, able to increase the molecular diagnosis performance, to facilitate the detection of copy number variants (CNV), to assess genetic risk scores (wGRS) and to offer the opportunity to explore candidate genes. Custom SeqCap EZ libraries, NextSeq500 sequencing and a homemade pipeline enable the analysis of 311 dyslipidemia-related genes. In the training group (48 DNA from patients with a well-established molecular diagnosis), this next-generation sequencing (NGS) workflow showed an analytical sensitivity >99% (n = 532 variants) without any false negative including a partial deletion of one exon. In the prospective group, from 25 DNA from patients without prior molecular analyses, 18 rare variants were identified in the first intention panel genes, allowing the diagnosis of monogenic dyslipidemia in 11 patients. In six other patients, the analysis of minor genes and wGRS determination provided a hypothesis to explain the dyslipidemia. Remaining data from the whole NGS workflow identified four patients with potentially deleterious variants. This NGS process gives a major opportunity to accede to an enhanced understanding of the genetic of dyslipidemia by simultaneous assessment of multiple genetic determinants.