scholarly journals Genotype–Phenotype Correlation in Children: The Impact of FBN1 Variants on Pediatric Marfan Care

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 799
Author(s):  
Veronika C. Stark ◽  
Flemming Hensen ◽  
Kerstin Kutsche ◽  
Fanny Kortüm ◽  
Jakob Olfe ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Splice Variants ◽  
Aortic Dilatation ◽  
Phenotype Correlation ◽  
Ectopia Lentis ◽  
Missense Variants ◽  
Genotype Phenotype Correlation ◽  
The Impact ◽  
Pulmonary Artery Dilatation

Currently, no reliable genotype–phenotype correlation is available for pediatric Marfan patients in everyday clinical practice. We investigated correlations of FBN1 variants with the prevalence and age of onset of Marfan manifestations in childhood and differentiated three groups: missense/in-frame, splice, and nonsense/frameshift variants. In addition, we differentiated missense variants destroying or generating a cysteine (cys-missense) and alterations not affecting cysteine. We categorized 105 FBN1-positive pediatric patients. Patients with cys-missense more frequently developed aortic dilatation (p = 0.03) requiring medication (p = 0.003), tricuspid valve prolapse (p = 0.03), and earlier onset of myopia (p = 0.02) than those with other missense variants. Missense variants correlated with a higher prevalence of ectopia lentis (p = 0.002) and earlier onset of pulmonary artery dilatation (p = 0.03) than nonsense/frameshift, and dural ectasia was more common in the latter (p = 0.005). Pectus excavatum (p = 0.007) appeared more often in patients with splice compared with missense/in-frame variants, while hernia (p = 0.04) appeared earlier in the latter. Findings on genotype–phenotype correlations in Marfan-affected children can improve interdisciplinary therapy. In patients with cys-missense variants, early medical treatment of aortic dilatation seems reasonable and early regular ophthalmologic follow-up essential. Patients with nonsense/frameshift and splice variants require early involvement of orthopedic specialists to support the growing child.

scholarly journals Genotype/Phenotype correlation and prognosis for undescribed ACTC1 missense variants

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.N Cicerchia ◽  
J.P Ochoa ◽  
I Cardenas-Reyes ◽  
G Fernandez Ferro ◽  
M.N Brogger ◽  
...  
Keyword(s):  
Sudden Death ◽  
Cardiovascular Death ◽  
Left Ventricular ◽  
Funding Source ◽  
Phenotype Correlation ◽  
Missense Variants ◽  
Septal Defects ◽  
Genotype Phenotype Correlation ◽  
Index Cases

Abstract Purpose Establish the genotype/phenotype correlation for missense undescribed variants in ACTC1, and evaluate their prognostic implications. Methods A systematic screening for the ACTC1 gene was performed using NGS in 17,683 individuals with inherited cardiovascular disease, 6,984 of them with hypertrophic cardiomyopathy, 3,507 with dilated cardiomyopathy, and 760 left ventricular non-compaction. These phenotypes were clinically diagnosed by each center prior to the genetic study. Frequency of the variants was compared with gene gnomAD and ClinVar databases. A systematic review of the literature was performed to search for previously reported variants. We evaluated available follow up data and constructed Kaplan-Meier survival curves free from cardiovascular death (sudden death, Heart transplant, heart failure death, appropriate ICD discharge and stroke related death). Log-rank test was used to compare event-free survival time between males and females. Results 39 missense variants were identified in 283 carriers (125 index cases; 158 first-degree relatives). Twenty-two have not been previously described or identified in public databases. 17 have been reported in gnomAD or Clinvar. Carriers phenotypes were: 120 HCM; 43 LVNC; 16 DCM; three had cardiac septal defect and two had sudden death. Some of the carriers had overlapped or combined phenotypes: 7 HCM and LVNC, 7 septal defects and LVNC, 3 HCM and septal defects, 4 MCD and LVNC. 24 were healthy carriers, and we have no phenotypic data of the remaining individuals. Family studies were performed in 12 families out of the 22 undescribed variants, showing cosegregation in 8 variants. One case was “de novo”. Interestingly, a rare variant, previously identified as VUS in ClinVar, showed a clearly cosegregation with HCM. The Leu10Met variant with a frequency of 9/282084 alleles in gnomAD (1/15671 individuals) was identified in 20 index cases, which represents 1/884 of all the genotyped (0.11%), and 1/387 patients with HCM (0.35%). We found it in 2/9289 patients with other phenotypes (p<0.001). 51 patients (18%) presented an event during follow up. In several cases, carriers developed early atrial fibrillation. The survival curve shows adverse events from the first decade of life, with a 10% cumulative rate of events at age 40, 80% survival at age 60, and a 60% survival at age 70. No significant differences in the incidence of cardiovascular death between men and women were observed. Conclusion HCM is the most frequent phenotype in carriers of ACTC1 variants, followed by LVNC, and DCM. Septal defects are not rare, and they are usually described in combination with cardiomyopathies. Disease course seems to have a good prognosis. Sudden death is an exception at early ages and appears to be associated with severe morphological expression. Given the presence of cosegregation with disease in rare variants, many of the ACTC1 variants may have an incomplete penetrance, and late disease expression. ACTC1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Health in Code

scholarly journals Genotype–phenotype correlation in WT1 exon 8 to 9 missense variants

2021 ◽  
Author(s):  
China Nagano ◽  
Yutaka Takaoka ◽  
Koichi Kamei ◽  
Riku Hamada ◽  
Daisuke Ichikawa ◽  
...  
Keyword(s):  
Phenotype Correlation ◽  
Missense Variants ◽  
Genotype Phenotype Correlation

The impact of Cannabis in Schizophrenia: Pafip Three-year Longitudinal Study on Outcome and Functionality After a First Episode of Psychosis

2017 ◽  
Vol 41 (S1) ◽  
pp. S136-S137
Author(s):  
M. Gomez Revuelta ◽  
M. Juncal Ruiz ◽  
O. Porta Olivares ◽  
M. Fernández Rodríguez ◽  
D. Abejas Díez ◽  
...  
Keyword(s):  
Intervention Program ◽  
Age Of Onset ◽  
Cannabis Use ◽  
First Episode ◽  
Long Term Outcome ◽  
Clinical Prognosis ◽  
Increased Risk ◽  
The Impact

IntroductionThe association between cannabis and psychosis makes crucial the intervention on cannabis use disorder at first episodes of psychosis (FEP), especially among young population. In this group of patients, the harmful potential of cannabis is more evident by its influence on neurodevelopment. However, the nature of the association cannabis-psychosis is not clearly described. It seems to represent a mediating factor for an increased risk of psychosis in healthy and high-risk populations, determining an earlier age of onset and worsening long term outcome.ObjectivesTo assess the impact of cannabis in terms of functional and clinical prognosis in patients recruited after a FEP.Material and methodsPAFIP is an early intervention program for early stages of psychosis. One hundred and sixty-three were included, followed-up at regular intervals of six months for three years with administration of clinical and functional scales (BPRS, SAPS, SANS, CDRS, GAF and Drake). Patients were divided into three groups: (1) those non-users neither before the onset nor during follow-up (nn) PEP, (2) consumers before the FEP and during follow-up (ss) and (3) consumers before the FEP that gave up consumption during follow-up (sn).ResultsNo statistically significant differences were observed in terms of functionality at three-year follow-up endpoint but a trend to a better-preserved functionality in the sn group. The sn group presented lower scores in scales for positive symptoms with respect to the comparison groups.ConclusionsThe interruption in cannabis use may have a beneficial effect on short-term clinical prognosis and functionality on long term.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals McArdle Disease: Clinical, Biochemical, Histological and Molecular Genetic Analysis of 60 Patients

Biomedicines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 33
Author(s):  
Pushpa Raj Joshi ◽  
Marcus Deschauer ◽  
Stephan Zierz
Keyword(s):  
Genetic Analysis ◽  
Age Of Onset ◽  
Molecular Genetic ◽  
Lactate Production ◽  
Molecular Genetic Analysis ◽  
Exercise Intolerance ◽  
Phenotype Correlation ◽  
Glycogen Accumulation ◽  
Mcardle Disease ◽  
Genotype Phenotype Correlation

A clinical, biochemical, histological and molecular genetic analysis of 60 McArdle patients (33 males and 27 females; mean age at diagnosis: 37 years) was performed. The objective of this study was to identify a possible genotype–phenotype correlation in McArdle disease. All patients complained of exercise-induced myalgia and fatigue; permanent weakness was present in 47% of the patients. Five percent of patients conveyed of masticatory muscle weakness. Age of onset was <15 years in 92% patients. Serum creatine kinase was elevated 5 to13-fold. Forearm ischemic test showed decreased lactate production but excessively increased ammonia upon exercise (n = 16). Muscle biopsies revealed highly reduced or missing myophosphorylase activity (n = 20) (mean: 0.17 ± 0.35 U/g tissue; normal: 12–61) and histologically, sub-sarcolemmal glycogen accumulation (n = 9). Molecular genetic analysis revealed the common p.Arg50Ter mutation in 68% of the patients. Other rather frequent mutations were p.Arg270Ter (allele frequency: 5%) followed by c.2262delA and p.Met1Val (allele frequencies: 3%). Twenty-four other rare mutations were also identified. No genotype–phenotype correlation was observed. The analysis highlights that testing of the p.Arg50Ter mutation could be performed first in molecular genetic testing of patients with exercise intolerance possibly due to McArdle disease. However, there is enormous mutation heterogeneity in McArdle disease thus sequencing of the myophosphorylase gene is needed in patients highly suspicious of McArdle disease.

scholarly journals The Role of Microtubule Associated Serine/Threonine Kinase 3 Variants in Neurodevelopmental Diseases: Genotype-Phenotype Association

2022 ◽  
Vol 14 ◽  
Author(s):  
Li Shu ◽  
Neng Xiao ◽  
Jiong Qin ◽  
Qi Tian ◽  
Yanghui Zhang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Large Scale ◽  
De Novo ◽  
Sequencing Data ◽  
Phenotype Correlation ◽  
Serine Threonine Kinase ◽  
Zebrafish Model ◽  
Threonine Kinase ◽  
Missense Variants ◽  
Genotype Phenotype Correlation

Objective: To prove microtubule associated serine/threonine kinase 3 (MAST3) gene is associated with neurodevelopmental diseases (NDD) and the genotype-phenotype correlation.Methods: Trio exome sequencing (trio ES) was performed on four NDD trios. Bioinformatic analysis was conducted based on large-scale genome sequencing data and human brain transcriptomic data. Further in vivo zebrafish studies were performed.Results: In our study, we identified four de novo MAST3 variants (NM_015016.1: c.302C &gt; T:p.Ser101Phe; c.311C &gt; T:p.Ser104Leu; c.1543G &gt; A:p.Gly515Ser; and c.1547T &gt; C:p.Leu516Pro) in four patients with developmental and epileptic encephalopathy (DEE) separately. Clinical heterogeneities were observed in patients carrying variants in domain of unknown function (DUF) and serine-threonine kinase (STK) domain separately. Using the published large-scale exome sequencing data, higher CADD scores of missense variants in DUF domain were found in NDD cohort compared with gnomAD database. In addition, we obtained an excess of missense variants in DUF domain when compared autistic spectrum disorder (ASD) cohort with gnomAD database, similarly an excess of missense variants in STK domain when compared DEE cohort with gnomAD database. Based on Brainspan datasets, we showed that MAST3 expression was significantly upregulated in ASD and DEE-related brain regions and was functionally linked with DEE genes. In zebrafish model, abnormal morphology of central nervous system was observed in mast3a/b crispants.Conclusion: Our results support the possibility that MAST3 is a novel gene associated with NDD which could expand the genetic spectrum for NDD. The genotype-phenotype correlation may contribute to future genetic counseling.

scholarly journals T88. THE IMPACT OF AGE OF ONSET AND ILLNESS DURATION ON WHITE MATTER AND COGNITION TRAJECTORIES IN SCHIZOPHRENIA: A 7-YEAR FOLLOW-UP STUDY ACROSS MULTIPLE TIME-POINTS

2019 ◽  
Vol 45 (Supplement_2) ◽  
pp. S237-S238
Author(s):  
Marie B Jensen ◽  
Bjørn H Ebdrup ◽  
Christos Pantelis ◽  
Mette Ø Nielsen ◽  
Jayachandra Mitta Raghava ◽  
...  
Keyword(s):  
White Matter ◽  
Age Of Onset ◽  
Multiple Time ◽  
Time Points ◽  
Illness Duration ◽  
Follow Up Study ◽  
Multiple Time Points ◽  
The Impact

scholarly journals Predictors of Treatment-Resistant and Clozapine-Resistant Schizophrenia: A 12-Year Follow-up Study of First-Episode Schizophrenia-Spectrum Disorders

2020 ◽  
Author(s):  
Sherry Kit Wa Chan ◽  
Hei Yan Veronica Chan ◽  
William G Honer ◽  
Tarun Bastiampillai ◽  
Yi Nam Suen ◽  
...  
Keyword(s):  
Social Adjustment ◽  
Age Of Onset ◽  
First Episode ◽  
Schizophrenia Spectrum Disorders ◽  
Treatment Resistant ◽  
Schizophrenia Spectrum ◽  
Spectrum Disorders ◽  
First Episode Schizophrenia ◽  
The Impact

Abstract Studies on the long-term development and early predictors of treatment-resistant schizophrenia (TRS) and clozapine-resistant TRS (CR-TRS) in patients with first-episode schizophrenia-spectrum disorders (FES) are limited and have not considered the impact of early intervention services (EIS). This study aimed to explore the development of TRS and CR-TRS among patients with FES over 12 years of follow-up. Of the 1234 patients with FES, 15% developed TRS. A total of 450 patients with schizophrenia or schizoaffective disorder were included in a nested case-control study (157 TRS and 293 non-TRS). Younger age of onset, poorer premorbid social adjustment during adulthood, longer duration of first episode, a greater number of relapses, and a higher antipsychotic dose in the first 24 months were associated with earlier TRS. CR-TRS patients, constituting 25% of TRS patients, had a poorer premorbid social adjustment in late adolescence and longer delay before clozapine initiation compared with non-CR-TRS. CR-TRS had poorer clinical and functional outcomes at 12-year follow-up. However, TRS patients on clozapine had a lower mortality rate compared with non-TRS patients. EIS did not have a significant impact on the development of TRS, but patients in the EIS group had a shorter delay of clozapine initiation. Results suggested that neurodevelopmental factors, early clinical characteristics, and requirement for higher antipsychotic dose may be associated with TRS development, highlighting multiple pathways leading to this form of illness. Specific interventions including relapse prevention and early initiation of clozapine during the early course of illness may reduce the rate of TRS and improve patient outcomes.

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