Tenorio syndrome (TNORS) (OMIM #616260) is a relatively recent disorder with very few cases described so far. Clinical features included macrocephaly, intellectual disability, hypotonia, enlarged ...ventricles and autoimmune diseases. Molecular underlying mechanism demonstrated missense variants and a large deletion encompassing RNF125, a gene that encodes for an U3 ubiquitin ligase protein. Since the initial description of the disorder in six patients from four families, several new patients were diagnosed, adding more evidence to the clinical spectrum. In this article, we described 14 additional cases with deep phenotyping and make an overall review of all the cases with pathogenic variants in RNF125. Not all patients presented with overgrowth, but instead, most patients showed a common pattern of neurodevelopmental disease, macrocephaly and/or large forehead. Segregation analysis showed that, though the variant was inherited in some patients from an apparently asymptomatic parent, deep phenotyping suggested a mild form of the disease in some of them. The mechanism underlying the development of this disease is not well understood yet and the report of further cases will help to a better understanding and clinical characterization of the syndrome.
Background: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH ...is not well known and genetics could influence management and prognosis. Objectives: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. Methods: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan–Meier curves. Results: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease—PVOD—in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders—MSD—in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was “reclassified”, with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. Conclusions: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.
Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by deficiencies in communication, social interaction, and repetitive and restrictive behaviors. The discovery of ...genetic involvement in the etiology of ASD has made this condition a strong candidate for genome-based diagnostic tests. Next-generation sequencing (NGS) is useful for the detection of variants in the sequence of different genes in ASD patients. Herein, we present the implementation of a personalized NGS panel for autism (AutismSeq) for patients with essential ASD over a prospective period of four years in the clinical routine of a tertiary hospital. The cohort is composed of 48 individuals, older than 3 years, who met the DSM-5 (The Diagnostic and Statistical Manual of Mental Disorders) diagnostic criteria for ASD. The NGS customized panel (AutismSeq) turned out to be a tool with good diagnostic efficacy in routine clinical care, where we detected 12 “pathogenic” (including pathogenic, likely pathogenic, and VUS (variant of uncertain significance) possibly pathogenic variations) in 11 individuals, and 11 VUS in 10 individuals, which had previously been negative for chromosomal microarray analysis and other previous genetic studies, such as karyotype, fragile-X, or MLPA/FISH (Multiplex Ligation dependent Probe Amplification/Fluorescence in situ hybridization) analysis. Our results demonstrate the high genetic and clinical heterogeneity of individuals with ASD and the current difficulty of molecular diagnosis. Our study also shows that an NGS-customized panel might be useful for diagnosing patients with essential/primary autism and that it is cost-effective for most genetic laboratories.
Autism spectrum disorders (ASD) comprise a group of neurodevelopmental disorders (NDD) characterized by deficits in communication and social interaction, as well as repetitive and restrictive ...behaviors, etc. The genetic implications of ASD have been widely documented, and numerous genes have been associated with it. The use of chromosomal microarray analysis (CMA) has proven to be a rapid and effective method for detecting both small and large deletions and duplications associated with ASD. In this article, we present the implementation of CMA as a first-tier test in our clinical laboratory for patients with primary ASD over a prospective period of four years. The cohort was composed of 212 individuals over 3 years of age, who met DSM-5 diagnostic criteria for ASD. The use of a customized array-CGH (comparative genomic hybridization) design (KaryoArray
) found 99 individuals (45.20%) with copy number variants (CNVs); 34 of them carried deletions (34.34%) and 65 duplications (65.65%). A total of 28 of 212 patients had pathogenic or likely pathogenic CNVs, representing approximately 13% of the cohort. In turn, 28 out of 212 (approximately 12%) had variants of uncertain clinical significance (VUS). Our findings involve clinically significant CNVs, known to cause ASD (syndromic and non-syndromic), and other CNVs previously related to other comorbidities such as epilepsy or intellectual disability (ID). Lastly, we observed new rearrangements that will enhance the information available and the collection of genes associated with this disorder. Our data also highlight that CMA could be very useful in diagnosing patients with essential/primary autism, and demonstrate the existence of substantial genetic and clinical heterogeneity in non-syndromic ASD individuals, underscoring the continued challenge for genetic laboratories in terms of its molecular diagnosis.
Pulmonary arterial hypertension is a very infrequent disease, with a variable etiology and clinical expressivity, making sometimes the clinical diagnosis a challenge. Current classification based on ...clinical features does not reflect the underlying molecular profiling of these groups. The advance in massive parallel sequencing in PAH has allowed for the describing of several new causative and susceptibility genes related to PAH, improving overall patient diagnosis. In order to address the molecular diagnosis of patients with PAH we designed, validated, and routinely applied a custom panel including 21 genes. Three hundred patients from the National Spanish PAH Registry (REHAP) were included in the analysis. A custom script was developed to annotate and filter the variants. Variant classification was performed according to the ACMG guidelines. Pathogenic and likely pathogenic variants have been found in 15% of the patients with 12% of variants of unknown significance (VUS). We have found variants in patients with connective tissue disease (CTD) and congenital heart disease (CHD). In addition, in a small proportion of patients (1.75%), we observed a possible digenic mode of inheritance. These results stand out the importance of the genetic testing of patients with associated forms of PAH (i.e., CHD and CTD) additionally to the classical IPAH and HPAH forms. Molecular confirmation of the clinical presumptive diagnosis is required in cases with a high clinical overlapping to carry out proper management and follow up of the individuals with the disease.
Reduced expression and/or activity of Kv1.5 channels (encoded by
) is a common hallmark in human or experimental pulmonary arterial hypertension (PAH). Likewise, genetic variants in
have been found ...in patients with PAH, but their functional consequences and potential impact on the disease are largely unknown. Herein, this study aimed to characterize the functional consequences of seven
variants found in a cohort of patients with PAH. Potassium currents were recorded by patch-clamp technique in HEK293 cells transfected with wild-type or mutant Kv1.5 cDNA. Flow cytometry, Western blot, and confocal microscopy techniques were used for measuring protein expression and cell apoptosis in HEK293 and human pulmonary artery smooth muscle cells.
variants (namely, Arg184Pro and Gly384Arg) found in patients with PAH resulted in a clear loss of potassium channel function as assessed by electrophysiological and molecular modeling analyses. The Arg184Pro variant also resulted in a pronounced reduction of Kv1.5 expression. Transfection with Arg184Pro or Gly384Arg variants decreased apoptosis of human pulmonary artery smooth muscle cells compared with the wild-type cells, demonstrating that
dysfunction in both variants affects cell viability. Thus, in addition to affecting channel activity, both variants were associated with impaired apoptosis, a crucial process linked to the disease. The estimated prevalence of dysfunctional
variants in the PAH population analyzed was around 1%. The data indicate that some
variants found in patients with PAH have critical consequences for channel function, supporting the idea that
pathogenic variants may be a causative or contributing factor for PAH.
Missense and frameshift pathogenic variants and microdeletions involving TBL1XR1 gene have been described in patients with intellectual disability, autism, Rett‐like features and schizophrenia, some ...of them with the clinical diagnosis of Pierpont syndrome, a rare pattern of multiple congenital anomalies, but others without dysmorphic findings or with non‐specific ones, and also patients with only some of the features associated with Pierpont syndrome. We here present a case with a de novo novel missense variant in TBL1XR1 gene with overlapping features with Pierpont syndrome and autism, a neurobehavioral manifestation not previously reported in Pierpont syndrome. This patient expands the phenotypic spectrum of TBL1XR1 gene pathogenic variants.
Pulmonary veno-occlusive disease (PVOD) is a very infrequent form of pulmonary arterial hypertension with an aggressive clinical course, poor response to specific vasodilator treatment, and low ...survival. Confirming a definitive diagnosis is essential to guide treatment and assess lung transplantation. However, in the absence of histological or genetic confirmation, the diagnosis is complex, requiring a clinical suspicion. Multidetector computed tomography (MDCT) is an essential part of the non-invasive diagnostic tools of PVOD. We retrospectively reviewed the MDCT findings from a consecutive series of 25 patients diagnosed with PVOD, 9 with the sporadic form and 16 with the hereditary form of the disease. The presence and extent of typical findings of the diagnostic triad were assessed in all patients (ground glass parenchymal involvement, septal lines, and lymphadenopathy). In our series, 92% of patients showed at least two of the radiological findings described as typical of the disease. All patients presented at least one typical radiological characteristic. The incidence of radiological findings considered typical is very high, however was not associated with greater hemodynamic severity nor to the development of acute lung edema. No significant differences were found between the two groups. A poorly expressive MDCT does not exclude the disease.
La evaluación del riesgo en la hipertensión arterial pulmonar (HAP) es esencial de cara a administrar un tratamiento más agresivo a aquellos pacientes de mayor riesgo. Sin embargo, las escalas ...pronósticas más recientes olvidan el trasfondo genético. Además, la enfermedad venooclusiva pulmonar (EVOP) no se ha considerado nunca en las estrategias de evaluación del riesgo.
Se consideraron para este trabajo pacientes consecutivos incluidos en el registro Español de HAP (REHAP) analizados genéticamente entre los años 2011 y 2022. Se aplicó en ellos el modelo COMPERA 2.0 de 4 estratos, comparando este resultado con el obtenido de un modelo ampliado que incluyó la genética. Se usaron modelos de regresión de Cox y el estadístico C de Harrel para comparar los distintos modelos. Se estudiaron específicamente estos modelos en la población EVOP antes de su inclusión.
Se seleccionaron 298 pacientes con HAP idiopática, familiar, inducida por fármacos y EVOP del registro REHAP. Considerando únicamente aquellos con todas las variables de interés disponibles al diagnóstico (clase funcional, prueba de la marcha de los 6 minutos, NT-proBNP o BNP), e incluidos en el modelo de 4 estratos (n=142), después de una mediana de seguimiento de 58,2 meses hasta el 17,6% de los pacientes fallecieron y un 11,3% necesitaron trasplante pulmonar. La aplicación del modelo de 4 estratos en nuestra población demostró una buena capacidad pronóstica (C de Harrel de 0,689). La introducción de la genética no mejoró ésta (índice C de 0,690). Este último modelo ampliado mostró una tendencia a una mejor identificación de pacientes en riesgo intermedio-bajo e intermedio-alto, sin diferencias en la identificación entre los estratos de riesgo intermedio-alto y alto.
En este trabajo la adición del resultado del estudio genético al modelo de 4 estratos COMPERA alcanzó una capacidad pronóstica total similar al modelo original, pero cambió la identificación de los estratos de riesgo en una cohorte de pacientes jóvenes analizados genéticamente.
Risk stratification in pulmonary arterial hypertension (PAH) is essential to provide more aggressive treatment for patients at higher risk. Nevertheless, recently introduced simplified prognostic tools neglect the genetic background. Additionally, pulmonary veno-oclusive disease (PVOD) has never been considered in risk assessment strategies.
We analyzed consecutive patients in the Spanish registry of PAH (REHAP) genetically tested, between 2011 and 2022. We applied the 4-strata COMPERA 2.0 model, comparing these results with an amplified score including genetics. Cox regression models were compared using Harrel c-statistics. The application of the model was specifically tested in PVOD before inclusion.
We identified 298 patients tested genetically among the group of idiopathic, familial, drug-induced PAH and PVOD patients in the REHAP registry. When we analyzed only patients with all available variables of interest at baseline (World Health Organization functional class, 6-minute walk test, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and included in the 4-strata model (n=142), after a median follow-up of 58.2 months, 17.6% of patients died and 11.3% underwent lung transplant. The application of the 4-strata model in our population demonstrated a good prognostic capacity (Harrel c of 0.689), which was not improved by the introduction of genetics (c-index 0.690). This last model showed a tendency for a better identification of patients at intermediate-low and intermediate-high risk, and no differences between intermediate-high and high-risk strata.
In this work, the addition of genetics to the COMPERA 4-strata model achieved a similar global prognostic capacity but changed the identification of different risk strata in a cohort of young genetically tested patients.
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