Case report: Identification of a novel variant p.Gly215Arg in the CHN1 gene causing Moebius syndrome.

Background: Moebius Syndrome (MBS) is a rare congenital neurological disorder characterized by paralysis of facial nerves, impairment of ocular abduction and other variable abnormalities. MBS has been attributed to both environmental and genetic factors as potential causes. Until now only two genes, PLXND1 and REV3L have been identified to cause MBS. Results: We present a 9-year-old male clinically diagnosed with MBS, presenting facial palsy, altered ocular mobility, microglossia, dental anomalies and congenital torticollis. Radiologically, he lacks both abducens nerves and shows altered symmetry of both facial and vestibulocochlear nerves. Whole-exome sequence identified a de novo missense variant c.643G>A; p.Gly215Arg in CHN1, encoding the α2-chimaerin protein. The p.Gly215Arg variant is located in the C1 domain of CHN1 where other pathogenic gain of function variants have been reported. Bioinformatic analysis and molecular structural modelling predict a deleterious effect of the missense variant on the protein function. Conclusion: Our findings support that pathogenic variants in the CHN1 gene may be responsible for different cranial congenital dysinnervation syndromes, including Moebius and Duane retraction syndromes. We propose to include CHN1 in the genetic diagnoses of MBS.

Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.

BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

High Performance of a Dominant/X-Linked Gene Panel in Patients with Neurodevelopmental Disorders.

Neurodevelopmental disorders (NDDs) affect 2-5% of the population and approximately 50% of cases are due to genetic factors. Since de novo pathogenic variants account for the majority of cases, a gene panel including 460 dominant and X-linked genes was designed and applied to 398 patients affected by intellectual disability (ID)/global developmental delay (GDD) and/or autism (ASD). Pathogenic variants were identified in 83 different genes showing the high genetic heterogeneity of NDDs. A molecular diagnosis was established in 28.6% of patients after high-depth sequencing and stringent variant filtering. Compared to other available gene panel solutions for NDD molecular diagnosis, our panel has a higher diagnostic yield for both ID/GDD and ASD. As reported previously, a significantly higher diagnostic yield was observed: (i) in patients affected by ID/GDD compared to those affected only by ASD, and (ii) in females despite the higher proportion of males among our patients. No differences in diagnostic rates were found between patients affected by different levels of ID severity. Interestingly, patients harboring pathogenic variants presented different phenotypic features, suggesting that deep phenotypic profiling may help in predicting the presence of a pathogenic variant. Despite the high performance of our panel, whole exome-sequencing (WES) approaches may represent a more robust solution. For this reason, we propose the list of genes included in our customized gene panel and the variant filtering procedure presented here as a first-tier approach for the molecular diagnosis of NDDs in WES studies.

Natural gene therapy by reverse mosaicism leads to improved hematology in Fanconi anemia patients.

Fanconi anemia (FA) is characterized by chromosome fragility, bone marrow failure (BMF) and predisposition to cancer. As reverse genetic mosaicism has been described as "natural gene therapy" in patients with FA, we sought to evaluate the clinical course of a cohort of FA mosaic patients followed at referral centers in Spain over a 30-year period. This cohort includes patients with a majority of T cells without chromosomal aberrations in the DEB-chromosomal breakage test. Relative to non-mosaic FA patients, we observed a higher proportion of adult patients in the cohort of mosaics, with a later age of hematologic onset and a milder evolution of (BMF). Consequently, the requirement for hematopoietic stem cell transplant (HSCT) was also lower. Additional studies allowed us to identify a sub-cohort of mosaic FA patients in whom the reversion was present in bone marrow (BM) progenitor cells leading to multilineage mosaicism. These multilineage mosaic patients are older, have a lower percentage of aberrant cells, have more stable hematology and none of them developed leukemia or myelodysplastic syndrome when compared to non-mosaics. In conclusion, our data indicate that reverse mosaicism is a good prognostic factor in FA and is associated with more favorable long-term clinical outcomes.

Identificación mediante secuenciación de nueva generación de dos nuevos casos de miocardiopatía no compactada asociada a deleciones 1p36 / Identification by next-generation sequencing of 2 novel cases of noncompaction cardiomyopathy associated with 1p36 deletions

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Factors Associated with Suicide Attempts and Suicides in the General Population of Andalusia (Spain).

Discrepant results have been published by studies comparing deaths by suicide with attempted suicides. This study aimed to determine factors associated with suicides and attempted suicides in Andalusia (Spain) between 2007 and 2013, comparing sex, age, year, and suicide method between these populations. A retrospective study was conducted of data on deaths by suicide and attempted suicides over a seven-year period, calculating the sex and age rates for each behavior. Adjusted Poisson regression was used to analyze the association with study variables, and incidence rate ratios were estimated. During the seven-year study period, 20,254 attempted suicides and 5202 deaths by suicide were recorded. The prevalence of attempted suicide did not differ between the sexes, whereas the prevalence of deaths by suicide was three-fold higher among males than among females and increased with higher age. The most frequently used method was the same in males and females for suicide attempts, but differed between the sexes for suicides. The combined influence of sex and age was greater in the model for death by suicide than in the model for attempted suicide. The key differentiating factor was the method used, while the finding of greatest concern was the suicide behavior among the elderly. Preventive strategies should take these differences into account.

Dos nuevos casos autosómicos recesivos del síndrome de Noonan asociados con variantes del gen LTZR1 / Two novel cases of autosomal recessive Noonan syndrome associated with LZTR1 variants

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Fenotipo incompleto de síndrome de Marfan tipo MASS: descripción de nueva variante patogénica del gen de la fibrilina-1 / Incomplete mass phenotype: description of a new pathogenic variant of the fibrillin-1 gene

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Síndrome de Brugada familiar asociado con una deleción completa de los genes SCN5A y SCN10A / Familial brugada syndrome associated with a complete deletion of the SCN5A and SCN10A genes

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Abordaje de las cardiopatías familiares desde la Medicina genómica / Approach to familial heart diseases from Genomic Medicine

Resumen Las cardiopatías familiares son un grupo de enfermedades con alta heterogeneidad clínica y genética. Debido a que pueden heredarse y a su asociación con la muerte súbita, se recomienda efectuar un estudio clínico y genético del individuo afectado y su familia a través de una unidad especializada. Con la implementación de la secuenciación masiva se ha facilitado el acceso a los estudios genéticos en la práctica clínica de forma más rutinaria. Sin embargo, dada la gran cantidad de información obtenida se hacen necesarios el análisis y la interpretación adecuada de los resultados para garantizar un diagnóstico correcto. Este nuevo modelo de medicina amplía nuestra comprensión sobre estas patologías, gracias a que optimiza el diagnóstico, da una mejor aproximación pronóstica de los pacientes e identifica individuos asintomáticos en riesgo. Este artículo pretende realizar una revisión de la arquitectura genética de las enfermedades cardíacas hereditarias y proporcionar un enfoque práctico acerca de la utilidad de la Medicina genómica en el diagnóstico, la estratificación del riesgo y el estudio familiar en pacientes con este tipo de patologías.

Abstract The familial heart diseases are a group of diseases with high clinical and genomic heterogeneity. As they can be inherited and are associated with sudden death, it is recommended to perform a clinical and genetic study of the individual affected, as well as the family, in a specialised unit. The implementation of massive sequencing has meant that access to genetic studies is available in the most routine clinical practice. However, due to the large amount of information obtained, the results have to analysed and interpreted to ensure a correct diagnosis. This new medicine model widens the understanding of these diseases, as due to the diagnosis being optimised, it provides a more accurate prognosis for the patients, and identifies asymptomatic individuals at risk. A review is presented on the genetic architecture of heritable heart disease and provides a practical approach on the usefulness of Genomic Medicine in the diagnosis, risk stratification, and the familial study in patients with these types of heart diseases.

A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome.

Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.

Suicide attempts in Spain according to prehospital healthcare emergency records.

OBJECTIVE: To analyze the number and characteristics of suicide attempts by reviewing records of the public emergency healthcare service information system. METHOD: A retrospective observational study was conducted of emergency telephone calls received between January 1 2007 and December 31 2013 throughout the Andalusia region (Southern Spain). Cases were selected based on phone operator or healthcare team labeling. Data were analyzed on the characteristics of the individuals, the timing and severity of attempts, their prioritization, and their outcome. RESULTS: Between January 1 2007 and December 31 2013, 20.942 calls related to suicide attempts were recorded, a rate of 34.7 attempts per 100,000 inhabitants. Most cases were classified by the public emergency healthcare service (Empresa Pública de Emergencias Sanitarias, EPES) as code X84 (The International Statistical Classification of Diseases, tenth revision, ICD-10) or 305(The International Statistical Classification of Diseases, ninth revision, ICD-9). Attempts were more frequent in the 35-49-year age group and there were similar proportions of males and females. The lowest number of calls for suicide attempts were in 2007 and the highest in 2013. Calls were more frequent during the summer months, at weekends, and between 16:00 and 23:00 h. The likelihood of evacuation to the hospital emergency department was almost two-fold lower in over 65-yr-olds than in younger individuals. Significant (Æ¿ = 0.001) gender differences were found in call outcome and prioritization. The most influential factor for evacuation to a hospital emergency department was the code assigned by the attending healthcare team. CONCLUSIONS: Information obtained from extra-hospital emergency services provides valuable data on the characteristics and timing of calls related to suicide attempts, complementing information from hospital emergency departments or population surveys. There is a need to standardize the definition and recording of a suicide attempt.

Extensa familia con síndrome de Marfan en la que se demuestra la patogenicidad de una variante «sinónima» (p. Ile2118=) en el gen de la fibrilina 1 / A large family with Marfan syndrome demonstrating the pathogenicity of a «synonymous» variant (p. ile2118=) in the fibrillin-1 gene

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