•Clinical parameters differ between ALS patients with short and long survival.•Pathogenic mutations are frequent at both edges, especially SOD1 variants.•Genetic architecture differs between ALS ...patients with short and long survival.•Genetic variants with slow disease progression may be a prognostically favorable.•Genetic variants with fast disease progression show earlier disease onset.
Patients with amyotrophic lateral sclerosis (ALS) show substantial differences in disease progression and survival. However, the genetic contribution to the extremes of this spectrum remains poorly characterized. We unbiasedly selected and genotyped 102 ALS patients with very short (<15 months) and 90 with very long survival (>100 months) from the ALS registry of Ulm University using whole-exome sequencing and C9orf72 repeat expansion testing followed by a clinicogenetic correlation analysis. Clinically, groups significantly differed regarding site of disease onset, age at onset, BMI at diagnosis, disease progression rates, and diagnostic latency. We found a monogenic disease cause in 31 patients (16%) without significant differences in patients with short and long survival (19% vs. 13%; p = 0.41), but differences in the genotypic architecture. C9orf72 expansions and FUS mutations were only found in fast progressors, whereas SOD1 variants were frequent in both groups contributing 52% of all monogenic cases–33% among fast and 75% among slow variants. Our genotype-phenotype correlation may be relevant for genetic counseling, estimation of prognosis, and therapeutic decisions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To evaluate a novel candidate disease gene, we engaged international collaborators and identified rare, biallelic, specifically homozygous, loss of function variants in SENP7 in four children from ...three unrelated families presenting with neurodevelopmental abnormalities, dysmorphism, and immunodeficiency. Their clinical presentations were characterized by hypogammaglobulinemia, intermittent neutropenia, and ultimately death in infancy for all four patients. SENP7 is a sentrin-specific protease involved in posttranslational modification of proteins essential for cell regulation, via a process referred to as deSUMOylation. We propose that deficiency of deSUMOylation may represent a novel mechanism of primary immunodeficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Este estudo analisa o Programa Esporte e Lazer da Cidade (Pelc), de responsabilidade do Ministério do Esporte (ME). A pesquisa utilizou categorias e indicadores propostos por Boschetti (2009). ...Identificamos o marco legal, a abrangência, os critérios de acesso e permanência, as formas de articulação com esferas do governo e organizações não governamentais. Constatamos a asfixia orçamentária vivenciada pelo programa – que deve persistir tendo em vista a realização dos megaeventos esportivos no país –, a dependência de emendas parlamentares, a dificuldade dos gestores em compreender o desenho conceitualinovador do Pelc, que prevê um modelo de gestão compartilhada, a auto-organização, o trabalho coletivo e a vivência dos conteúdos do lazer de forma intergeracional.
•Variants in TAB2 can cause isolated or syndromic CHD.•TAB2-associated CHD has variable expressivity as well as reduced penetrance.•There is no clear genotype-phenotype correlation.
Congenital heart ...defects (CHD) are the most common birth defect and disease-causing variant in TAB2 have found to be associated with isolated CHD. Recently, it became evident that pathogenic, mostly loss-of-function variants in TAB2 can also cause syndromic CHD that includes connective tissue anomalies. The number of published cases is limited posing a challenge for counseling affected patients and their relatives.
Cases in whom whole exome sequencing was executed at our institute between January 2015 and June 2021 were screened for disease-causing variants in TAB2. Additionally, a PubMed-based review of the literature was performed in December 2021 in order to give an updated clinical overview of the TAB2-associated phenotypic spectrum, including our cases.
We identified three cases with syndromic CHD caused by different heterozygous loss-of-function variants in TAB2. In one of these cases, the variant was inherited by a healthy father. A comparison with published cases highlights that most patients were affected by structural and/or arrhythmic heart disease (about 90%) while about two third of all cases had syndromic comorbidity especially connective tissue defects and dysmorphic abnormalities.
Our findings indicate a variable expressivity as well as reduced penetrance of TAB2-associated CHD. Disease-causing variants in TAB2 should be considered in cases with isolated CHD but also in syndromic CHD with connective tissue abnormalities. However, prediction of the patients’ clinical outcome solely based on the variant in TAB2 is still extremely challenging.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals ...that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders.
Cross-sectional cohort study.
174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and “other.”
A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing–solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n=5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases.
The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease).
Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.
Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone ...lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003)-being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.
O estudo investiga as características da política econômica, social e, sobretudo, esportiva nos dois primeiros anos do governo Bolsonaro. Para tanto foi desenvolvido debate teórico e estudo ...documental, com análise da legislação esportiva e do montante e a destinação dos recursos do governo federal para o esporte. Observou-se que não houve novos ordenamentos com impacto significativo para o campo esportivo. Quanto ao orçamento, percebeu-se uma queda do montante nestes dois anos em relação aos governos anteriores e a priorização do esporte de alto rendimento.
Variants in γ‐aminobutyric acid A (GABAA) receptor genes cause different forms of epilepsy and neurodevelopmental disorders. To date, GABRA4, encoding the α4‐subunit, has not been associated with a ...monogenic condition. However, preclinical evidence points toward seizure susceptibility. Here, we report a de novo missense variant in GABRA4 (c.899C>T, p.Thr300Ile) in an individual with early‐onset drug‐resistant epilepsy and neurodevelopmental abnormalities. An electrophysiological characterization of the variant, which is located in the pore‐forming domain, shows accelerated desensitization and a lack of seizure‐protective neurosteroid function. In conclusion, our findings strongly suggest an association between de novo variation in GABRA4 and a neurodevelopmental disorder with epilepsy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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