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PloS One 2022To systematically review the relationship between genotypes and clinical phenotypes of Familial exudative vitreoretinopathy (FEVR) to support risk estimation and... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To systematically review the relationship between genotypes and clinical phenotypes of Familial exudative vitreoretinopathy (FEVR) to support risk estimation and therapeutic decisions.
DESIGN
Systematic review with meta-analysis.
DATA SOURCES
The data of our study were collected from PubMed, Embase, Web of Science, Cochrane, CBM, China National Knowledge Infrastructure (CNKI), WAN FANG and VIP databases since inception to August 2021.
RESULTS
A total of 3257 patients from 32 studies were included according to the inclusion and exclusion criteria. Among all the cases, the mutation frequencies of LRP5, FZD4, NDP, TSPAN12, ZNF408 and KIF11 were 13.6%, 11.5%, 4.6%, 6.7%, 1.6%, and 5.7%, respectively. We found that the patients with NDP and FZD4 suffer more severe symptoms, among which 86.4% patients of NDP and 78.6% patients of FZD4 were in the advanced stage of FEVR. Retinal detachment is the most frequent symptom with patients of LRP5 and NDP mutations, accounting for 51.9% and 64.5%, respectively. For the patients with the mutation of TSPAN12, retinal fold is the most common clinical manifestation, and suffer the mildest clinical phenotypes compared with the other three genes.
CONCLUSION
The results of the meta-analysis indicate that different types of genetic mutations occur at different frequencies. In addition, the clinical manifestations of FEVR are related to the type of gene mutation. Therefore, targeted treatment strategies and follow-up recommendations should be adopted for different pathogenic genes of FEVR.
Topics: DNA Mutational Analysis; DNA-Binding Proteins; Eye Diseases, Hereditary; Familial Exudative Vitreoretinopathies; Frizzled Receptors; Genetic Association Studies; Humans; Low Density Lipoprotein Receptor-Related Protein-5; Mutation; Pedigree; Retinal Diseases; Tetraspanins; Transcription Factors
PubMed: 35830446
DOI: 10.1371/journal.pone.0271326 -
BMC Medical Genomics Apr 2023Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner...
BACKGROUND
Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review.
METHODS
We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review.
RESULTS
One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7-9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI.
CONCLUSIONS
We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.
Topics: Humans; Wolfram Syndrome; Cochlear Implants; Cochlear Implantation; Pedigree; Hearing Loss; Deafness
PubMed: 37041640
DOI: 10.1186/s12920-023-01506-x -
Frontiers in Immunology 2022Haploinsufficiency of A20 (HA20) is a newly described rare autoinflammatory disease caused by gene mutations. HA20 has seldom been documented in the Chinese population....
OBJECTIVE
Haploinsufficiency of A20 (HA20) is a newly described rare autoinflammatory disease caused by gene mutations. HA20 has seldom been documented in the Chinese population. Herein, we report eight patients with HA20 from three unrelated families in China.
METHODS
Eight Chinese Han patients were diagnosed with HA20 in our department from 2018 to 2021. Their clinical data and genotypes were carefully documented and studied. The newly identified variants were functionally verified. We also conducted a systematic literature review of HA20, and the clinical characteristics and genotype of HA20 between the Chinese population and other populations were compared.
RESULTS
Eight HA20 patients from three families comprised six adults and two children. There was one man and seven women. The clinical characteristics included recurrent oral ulcers (8/8, 100%), fever (4/8, 50%), perianal ulcer (3/8, 38%), skin lesions (2/8, 25%), arthritis (1/8, 13%), and uveitis (1/8, 13%). Three variants, A547T, c.1906+2T>G, and R271X, were identified. Two novel variants, A547T and c.1906+2T>G, were validated to be pathogenic in our study. In a literature review a total of 126 patients with HA20 reported by 35 articles were included. The clinical phenotype of Chinese HA20 patients was similar to that of patients from other populations except for a lower frequency of genital ulcers (16.7% vs. 54.4%, p < 0.01). Autoantibodies were detectable in approximately one-third of the 126 patients, among which ANA and anti-thyroid antibodies were commonly seen.
CONCLUSION
The rarity and diversity of phenotypes make the diagnosis of HA20 a huge challenge to physicians. HA20 should be considered in child-onset patients with manifestations that resemble Behçet's syndrome, especially those whose family members have similar symptoms. Gene testing is critically helpful for the diagnosis of HA20. Two novel variants, A547T and c.1906+2T>G, were identified in this study.
Topics: Asian People; Cytokines; Female; Haploinsufficiency; Humans; Pedigree; Phenotype
PubMed: 35958611
DOI: 10.3389/fimmu.2022.955079 -
Journal of the Formosan Medical... Feb 2016There are great diversities of clinical phenotypes among the various familial Alzheimer's disease (FAD) families. We aimed to systematically review all the previously... (Review)
Review
There are great diversities of clinical phenotypes among the various familial Alzheimer's disease (FAD) families. We aimed to systematically review all the previously reported cases of FAD and to perform comparisons between Asian and white patients. In this regard, we collected individual-level data from 658 pedigrees. We found that patients with presenilin 1 (PSEN1) mutations had the earliest age of onset (AOO; 43.3 ± 8.6 years, p < 0.001) and were more commonly affected by seizures, spastic paraparesis, myoclonus, and cerebellar signs (p < 0.001, p < 0.001, p = 0.003, and p = 0.002, respectively). Patients with PSEN2 mutations have a delayed AOO with longest disease duration and presented more frequently with disorientation (p = 0.03). Patients with amyloid precursor protein (APP) mutations presented more frequently with aggression (p = 0.02) and those with APP duplication presented more frequently with apraxia (p = 0.03). PSEN1 mutations before codon 200 had an earlier AOO than those having mutations after codon 200 (41.4 ± 8.0 years vs. 44.7 ± 8.7 years, p < 0.001). Because 42.9% of the mutations reported are novel, the mutation spectrum and clinical features in Asian FAD families could be different from that of whites. Asian patients with PSEN1 mutations presented more frequently with disorientation (p = 0.02) and personality change (p = 0.01) but less frequently with atypical clinical features. Asian patients with APP mutations presented less frequently with aphasia (p = 0.02). Thus, clinical features could be modified by underlying mutations, and Asian FAD patients may have different clinical features when compared with whites.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Asian People; Humans; Mutation; Pedigree; Presenilin-1; Presenilin-2; Taiwan
PubMed: 26337232
DOI: 10.1016/j.jfma.2015.08.004 -
Journal of the American Heart... Jun 2021Background Brugada syndrome is an inherited cardiac channelopathy associated with major arrhythmic events (MAEs). The presence of a positive family history of sudden... (Meta-Analysis)
Meta-Analysis
Background Brugada syndrome is an inherited cardiac channelopathy associated with major arrhythmic events (MAEs). The presence of a positive family history of sudden cardiac death (SCD) as a risk predictor of MAE remains controversial. We aimed to examine the association between family history of SCD and MAEs stratified by age of SCD with a systematic review and meta-analysis. Methods and Results We searched the databases of MEDLINE and EMBASE from January 1992 to January 2020. Data from each study were combined using the random-effects model. Fitted metaregression was performed to evaluate the association between the age of SCD in families and the risk of MAE. Twenty-two studies from 2004 to 2019 were included in this meta-analysis involving 3386 patients with Brugada syndrome. The overall family history of SCD was not associated with increased risk of MAE in Brugada syndrome (pooled odds ratio [OR], 1.11; 95% CI, 0.82-1.51; =0.489, I=45.0%). However, a history of SCD in family members of age younger than 40 years of age did increase the risk of MAE by ≈2-fold (pooled OR, 2.03; 95% CI, 1.11-3.73; =0.022, I=0.0%). When stratified by the age of cut point at 50, 45, 40, and 35 years old, a history of SCD in younger family member was significantly associated with a higher risk of MAE (pooled OR, 0.49, 1.30, 1.51, and 2.97, respectively; =0.046). Conclusions A history of SCD among family members of age younger than 40 years was associated with a higher risk of MAE.
Topics: Brugada Syndrome; Death, Sudden, Cardiac; Electrocardiography; Family; Global Health; Humans; Incidence; Pedigree; Risk Factors; Survival Rate
PubMed: 34013737
DOI: 10.1161/JAHA.120.019788 -
Endocrine Dec 2020Apparent mineralocorticoid excess (AME) is an ultrarare autosomal recessive disorder resulting from deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2)...
PURPOSE
Apparent mineralocorticoid excess (AME) is an ultrarare autosomal recessive disorder resulting from deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) caused by mutations in HSD11B2. The purpose of this study was to identify novel compound heterozygous HSD11B2 mutations in a Chinese pedigree with AME and conduct a systematic review evaluating the AME clinical features associated with HSD11B2 mutations.
METHODS
Next-generation sequencing was performed in the proband, and Sanger sequencing was used to identify candidate variants in family members, 100 hypertensives, and 100 healthy controls. A predicted structure of 11βHSD2 was constructed by in silico modeling. A systematic review was used to identify cases of HSD11B2-related AME. Data for genotyping and clinical characterizations and complications were extracted.
RESULTS
Next-generation sequencing showed novel compound heterozygous mutations (c.343_348del and c.1099_1101del) in the proband with early-onset hypertension and hypokalemia. Sanger sequencing verified the monoallelic form of the same mutations in five other relatives but not in 100 hypertensives or 100 healthy subjects. In silico structural modeling showed that compound mutations may simultaneously perturb the substrate and coenzyme binding pocket. A systematic review of 101 AME patients with 54 HSD11B2 mutations revealed early-onset hypertension, hypokalemia and homozygous mutations as common features. The homozygous HSD11B2 mutations correlated with low birth weight (r = 0.285, P = 0.02).
CONCLUSIONS
We report novel compound heterozygous HSD11B2 mutations in a Chinese teenager with early-onset hypertension, and enriched genotypic and phenotypic spectrums in AME. Genetic testing helps early diagnosis and treatment for AME patients, which may avoid target organ damage.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Adolescent; Humans; Hypertension; Hypokalemia; Mineralocorticoid Excess Syndrome, Apparent; Mutation
PubMed: 32816205
DOI: 10.1007/s12020-020-02460-9 -
Heart (British Cardiac Society) Jun 2022Bicuspid aortic valve (BAV) affects 1% of the general population. was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed...
INTRODUCTION
Bicuspid aortic valve (BAV) affects 1% of the general population. was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to mutations has not been estimated.
AIM
The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to mutations.
METHODS
The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting sequencing in context of congenital heart disease.
RESULTS
sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic mutations was observed in almost half of reported pedigrees.
CONCLUSIONS
Pathogenic and likely pathogenic genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.
Topics: Aortic Valve; Bicuspid Aortic Valve Disease; Heart Valve Diseases; Humans; Mutation; Pedigree; Receptor, Notch1
PubMed: 35288444
DOI: 10.1136/heartjnl-2021-320428 -
BMC Ophthalmology Apr 2024The goal of the study was to search for novel bi-allelic CRB1 mutations, and then to analyze the CRB1 literature at the genotypic and phenotypic levels. (Meta-Analysis)
Meta-Analysis
PURPOSE
The goal of the study was to search for novel bi-allelic CRB1 mutations, and then to analyze the CRB1 literature at the genotypic and phenotypic levels.
APPROACH
We screened various variables such as the CRB1 mutation types, domains, exons, and genotypes and their relation with specific ocular phenotypes. An emphasis was given to the bi-allelic missense and nonsense mutations because of their high prevalence compared to other mutation types. Finally, we quantified the effect of various non-modifiable factors over the best-corrected visual acuity oculus uterque (BCVA OU) using multivariate linear regression models and identified genetic interactions.
RESULTS
A novel bi-allelic missense in the exon 9 of CRB1; c.2936G > A; p.(Gly979Asp) was found to be associated with rod-cone dystrophy (RCD). CRB1 mutation type, exons, domains, and genotype distribution varied significantly according to fundus characteristics, such as peripheral pigmentation and condition, optic disc, vessels, macular condition, and pigmentation (P < 0.05). Of the 154 articles retrieved from PubMed, 96 studies with 439 bi-allelic CRB1 patients were included. Missense mutations were significantly associated with an absence of macular pigments, pale optic disc, and periphery pigmentation, resulting in a higher risk of RCD (P < 0.05). In contrast, homozygous nonsense mutations were associated with macular pigments, periphery pigments, and a high risk of LCA (P < 0.05) and increased BCVA OU levels. We found that age, mutation types, and inherited retinal diseases were critical determinants of BCVA OU as they significantly increased it by 33% 26%, and 38%, respectively (P < 0.05). Loss of function alleles additively increased the risk of LCA, with nonsense having a more profound effect than indels. Finally, our analysis showed that p.(Cys948Tyr) and p.(Lys801Ter) and p.(Lys801Ter); p.(Cys896Ter) might interact to modify BCVA OU levels.
CONCLUSION
This meta-analysis updated the literature and identified genotype-phenotype associations in bi-allelic CRB1 patients.
Topics: Humans; Alleles; Codon, Nonsense; Nerve Tissue Proteins; Genetic Association Studies; Retina; Phenotype; Mutation; Eye Proteins; Pedigree; DNA Mutational Analysis; Membrane Proteins
PubMed: 38622537
DOI: 10.1186/s12886-024-03419-4 -
BMC Cardiovascular Disorders Feb 2018Myxomatous mitral valve prolapse is a common cardiac abnormality. Morbus Barlow is characterized by excess myxomatous leaflet tissue, bileaflet prolapse or billowing,...
BACKGROUND
Myxomatous mitral valve prolapse is a common cardiac abnormality. Morbus Barlow is characterized by excess myxomatous leaflet tissue, bileaflet prolapse or billowing, chordae elongation and annular dilatation with or without calcification. Extensive myxoid degeneration with destruction of the normal three-layered leaflet tissue architecture is observed histologically in such patients. Autosomal dominant inheritance with an age and sex-dependent expression has long been recognised. This review explores the current understanding of the genetics of bileaflet prolapse, with a focus on genetic analysis and the role for echocardiographical screening of the first degree relatives of affected patients.
METHODS
Systematic literature searches were performed using PubMed and Embase up to September 2017. In Disse et al.'s study (study one) first degree relatives of 25 patients with Morbus Barlow who underwent mitral valve repair were screened for bileaflet valve prolapse. In Nesta et al.'s study one family with three living generations of 43 individuals with 9 confirmed cases of MVP was screened. Genotyping was performed in four families for 344 microsatellite markers from Chromosome 1 to 16.
RESULTS
In study one, autosomal dominant inheritance was shown in four pedigrees. Genome-wide linkage analysis of the most informative pedigree (24 individuals, three generations) showed a significant linkage for markers mapping to chromosome 16p. Linkage to this locus was confirmed in a second family within the same study, but was excluded in the remaining two pedigrees. In study two an autosomal dominant locus was mapped to chromosome 13. 8 of the 9 individuals affected were found to suffer from bileaflet prolapse.
CONCLUSIONS
Barlow's disease is a heritable trait but the genetic causes remain largely elusive. Ch16p11.2-p12.1 is the only locus proven to be associated with bileaflet prolapse. Locus 13.q31.3-q32.1 was shown to cause bileaflet as well as posterior leaflet prolapse. This review intends to make physicians aware of genetic causes of myxomatous mitral valve prolapse, thereby emphasising the importance of cardiological examination of first-degree relatives of patients with Morbus Barlow. Integrated and more comprehensive studies are needed for identification of genes involved in this heterogenic disease. Further genomic studies may facilitate more individualised and accurate risk assessment and may help to develop possible preventive stategies for patients in the future.
Topics: Adult; Echocardiography; Female; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study; Heredity; Humans; Male; Middle Aged; Mitral Valve; Mitral Valve Prolapse; Pedigree; Prognosis; Risk Factors
PubMed: 29486707
DOI: 10.1186/s12872-018-0755-y -
Circulation. Genomic and Precision... Nov 2019The prevalence of familial hypercholesterolemia is 1 in 250, but <10% of patients are diagnosed. Cascade testing enables early detection of cases through systematic...
BACKGROUND
The prevalence of familial hypercholesterolemia is 1 in 250, but <10% of patients are diagnosed. Cascade testing enables early detection of cases through systematic family tracing. Establishment of familial hypercholesterolemia cascade testing programs in the US could be informed by approaches used elsewhere.
METHODS
We conducted a systematic review of published studies in the English language of cascade testing for familial hypercholesterolemia, which reported the number of index cases and number of relatives tested and specified methods of contacting relatives and testing modalities methods utilized. For each study, we calculated yield (proportion of relatives who test positive) and new cases per index case, to facilitate comparison.
RESULTS
We identified 10 studies from the literature that met inclusion criteria; the mean number of probands and relatives per study was 242 and 826, respectively. The average yield was 44.76% with a range of 30% to 60.5%, and the mean new cases per index case was 1.65 with a range of 0.22 to 8.0. New cases per index case tended to be greater in studies that used direct contact versus indirect contact (2.06 versus 0.86), tested beyond first-degree relatives versus only first-degree relatives (3.65 versus 0.80), used active sample collection versus collection at clinic (4.11 versus 1.06), and utilized genetic testing versus biochemical testing (2.47 versus 0.42).
CONCLUSIONS
New case detection in familial hypercholesterolemia cascade testing programs tended to be higher with direct contact of relatives, testing beyond first-degree relatives, in-home-based sample collection, and genetic testing. These findings should be helpful for establishing cascade testing programs in the United States.
Topics: Apolipoproteins B; Genetic Testing; Humans; Hyperlipoproteinemia Type II; Mutation; Pedigree; Proprotein Convertase 9; Receptors, LDL
PubMed: 31638829
DOI: 10.1161/CIRCGEN.119.002723