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European Journal of Medical Genetics Oct 2021Hereditary Diffuse Gastric Cancer (HDGC) is a cancer predisposing syndrome mainly caused by germline inactivating variants in CDH1, encoding E-cadherin. Early-onset...
Hereditary Diffuse Gastric Cancer (HDGC) is a cancer predisposing syndrome mainly caused by germline inactivating variants in CDH1, encoding E-cadherin. Early-onset diffuse gastric cancer (DGC) and/or invasive lobular breast cancer (LBC) are the main phenotypes in CDH1-associated HDGC. CTNNA1, encoding for α-E-catenin, and E-cadherin-partner in the adherens junction complex, has been recently classified as a HDGC predisposing gene. Nevertheless, little is known about CTNNA1 tumor spectrum in variant carriers and variant-type associated causality. Herein, we systematically reviewed the literature searching for CTNNA1 germline variants carriers, further categorized them according to HDGC clinical criteria (HDGC vs non-HDGC), collected phenotypes, classified variants molecularly and according to CDH1 ACMG/AMP guidelines and performed genotype-phenotype analysis. We found 41 families carrying CTNNA1 germline variants encompassing in total 105 probands and relatives. All probands from 13 HDGC families presented DGC and their average age of onset was 40 ± 17 years; 10/13 (77%) HDGC families carried a pathogenic (P) variant. Most probands from 28 non-HDGC families developed unspecified-BC, as well as most of their relatives; 4/28 (14%) carried a P variant, 16/28 (57%) carried a likely pathogenic (LP) variant, 7/28 (25%) carried variants of unknown significance (VUS) and 1/28 (4%) carried a likely benign variant. Regardless of clinical criteria, 97% (32/33) of probands and relatives from P variant-carrier families had DGC/unspecified-GC. In LP variant-carrier families, 82% (28/34) of probands and relatives had unspecified-BC. Only 2/105 individuals had LBC. A cluster of frameshift and nonsense variants was found in CTNNA1 last exon of non-HDGC families and classified as VUS. In conclusion, current available data confirms an association of CTNNA1 P variants with early-onset DGC, but not with LBC. We demonstrate that in ascertained cohorts, CTNNA1 P variants explain <2% of HDGC families and support the use of ACMG/AMP CDH1 specific variant curation guidelines, while no specific guidelines are developed for CTNNA1 variant classification. Moreover, we demonstrated that truncating variants at the CTNNA1 NMD-incompetent last exon have limited deleteriousness, and that CTNNA1 LP variants have lower actionability than CDH1 LP variants. Current knowledge supports considering only CTNNA1 P variants as clinically actionable in HDGC carrying families.
Topics: Antigens, CD; Cadherins; Gene Frequency; Genetic Predisposition to Disease; Germ-Line Mutation; Heterozygote; Humans; Pedigree; Phenotype; Stomach Neoplasms; alpha Catenin
PubMed: 34425242
DOI: 10.1016/j.ejmg.2021.104316 -
Journal of Cancer Research and Clinical... Nov 2023The objective of this study was to determine the male and female frequency of diffuse gastric cancer (DGC), the age at diagnosis, and the country of origin in a selected... (Review)
Review
PURPOSE
The objective of this study was to determine the male and female frequency of diffuse gastric cancer (DGC), the age at diagnosis, and the country of origin in a selected population with germline CDH1 variants from families with the hereditary diffuse gastric cancer (HDGC) syndrome.
METHODS
Relevant literature dating from 1998 to 2021 was systematically searched for data on CDH1 gene. The Wilcoxon rank sum test and the Chi-square test were used to estimate if the difference observed between patients with gastric cancer (GC) and unaffected individuals was significant.
RESULTS
We identified 80 families fulfilling the established clinical criteria for HDGC CDH1 genetic screening. There were more women than men with DGC and germline CDH1 variant (65.5%). Stratifying the age at diagnosis, we identified an association between DGC, positive CDH1 screening and young women (≤ 40 years) (p = 0.015). The mean age at diagnosis was 39.6 ys for women and 42.5 ys for men. There was an association between CDH1 carrier status and DGC (p = 0.021).
CONCLUSIONS
Young women carrying germline CDH1 variants with DGC are comparatively frequent in the HDGC syndrome, and potentially at higher risk to develop DGC particularly in low-incidence areas for GC.
Topics: Humans; Male; Female; Infant; Stomach Neoplasms; Pedigree; Genetic Testing; Adenocarcinoma; Germ Cells; Cadherins; Germ-Line Mutation; Genetic Predisposition to Disease; Antigens, CD
PubMed: 37639007
DOI: 10.1007/s00432-023-05318-5 -
Circulation Jan 2024Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted.
METHODS
A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up.
RESULTS
In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for (myosin light chain 3) to ≈55% for (myosin-binding protein C3), ≈60% for (troponin T2) and (troponin I3), and ≈65% for (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for and ≈23% for .
CONCLUSIONS
The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.
Topics: Humans; Adult; Penetrance; Mutation; Cross-Sectional Studies; Pedigree; Cardiomyopathy, Hypertrophic; Troponin T
PubMed: 37929589
DOI: 10.1161/CIRCULATIONAHA.123.065987 -
BioMed Research International 2023LHON is a progressive disease with early disease onset and male predominance, usually causing devastating visual loss to patients. These systematic review and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
LHON is a progressive disease with early disease onset and male predominance, usually causing devastating visual loss to patients. These systematic review and meta-analysis are aimed at summarizing epidemiology, disease onset and progression, visual recovery, risk factors, and treatment options of Leber's hereditary optic neuropathy (LHON) with mitochondrial DNA mutation G11778A from current evidence.
METHODS
The PubMed database was examined from its inception date to November 2021. Data from included studies were pooled with either a fixed-effects model or a random-effects model, depending on the results of heterogeneity tests. Sensitivity analysis was conducted to test the robustness of results.
RESULTS
A total of 41 articles were included in the systematic review for qualitative analysis, and 34 articles were included for quantitative meta-analysis. The pooled estimate of proportion of G11778A mutation among the three primary mutations of mitochondrial DNA (G11778A, G3460A, and T14484C) for LHON was 73% (95% CI: 67% and 79%), and the LHON patients with G11778A mutation included the pooled male ratio estimate of 77% (76% and 79%), the pooled age estimate of 35.3 years (33.2 years and 37.3 years), the pooled onset age estimate of 22.1 years (19.7 years and 24.6 years), the pooled visual acuity estimate of 1.4 LogMAR (1.2 LogMAR and 1.6 LogMAR), and the pooled estimate of spontaneous visual recovery rate (in either 1 eye) of 20% (15% and 27%).
CONCLUSIONS
The G11778A mutation is a prevalent mitochondrial DNA mutation accounting for over half of LHON cases with three primary mutations. Spontaneous visual recovery is rare, and no effective treatment is currently available.
Topics: Adult; Female; Humans; Male; Young Adult; DNA, Mitochondrial; Mitochondria; Mutation; Optic Atrophy, Hereditary, Leber; Pedigree
PubMed: 36743514
DOI: 10.1155/2023/1107866 -
Movement Disorders : Official Journal... Jan 2022Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration.
BACKGROUND
Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration.
OBJECTIVES
The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported.
METHODS
We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review.
RESULTS
PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating, which may explain the phenotypic heterogeneity of childhood- and late-onset PLA2G6-associated neurodegeneration. In five deceased patients, median disease duration was 13.0 years. Brain pathology in three cases showed mixed Lewy and tau pathology.
CONCLUSIONS
Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not. Early, severe dyskinesias are a tell-tale sign. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Age of Onset; Atrophy; Dystonia; Genotype; Group VI Phospholipases A2; Humans; Mutation; Parkinsonian Disorders; Pedigree; Phenotype
PubMed: 34622992
DOI: 10.1002/mds.28807 -
Molecular Syndromology Apr 2021Pierre Robin syndrome/sequence (PRS) is associated with a triad of symptoms that includes micrognathia, cleft palate, and glossoptosis that may lead to respiratory... (Review)
Review
Pierre Robin syndrome/sequence (PRS) is associated with a triad of symptoms that includes micrognathia, cleft palate, and glossoptosis that may lead to respiratory obstruction. The syndrome occurs in 2 forms: nonsyndromic PRS (nsPRS), and PRS associated with other syndromes (sPRS). Studies have shown varying genetic mutations associated with both nsPRS and sPRS. The present systematic review aims to provide a comprehensive collection of published literature reporting genetic mutations in PRS. Web of Science, PubMed, and Scopus were searched using the keywords: "Pierre Robin syndrome/sequence AND gene mutation." The search resulted in 208 articles, of which 93 were excluded as they were duplicates/irrelevant. The full-text assessment led to the further exclusion of 76 articles. From the remaining 39 articles included in the review, details of 324 cases were extracted. 56% of the cases were sPRS, and 22% of the cases were associated with other malformations and the remaining were nsPRS. Genetic mutations were noted in 30.9% of the 300 cases. Based on the review, was found to be the most common gene associated with both nsPRS and sPRS. The gene mutation in sPRS was specific to the associated syndrome. Due to the lack of original studies, a quantitative analysis was not possible. Thus, future studies must focus on conducting large-scale cohort studies. Along with generating data on genetic mutation, future studies must also conduct pedigree analysis to assess potential familial inheritance, which in turn could provide valuable insights into the etiopathogenesis of PRS.
PubMed: 34012376
DOI: 10.1159/000513217 -
PloS One 2024Many forms of childhood glaucoma have been associated with underlying genetic changes, and variants in many genes have been described. Currently, testing is variable as...
Many forms of childhood glaucoma have been associated with underlying genetic changes, and variants in many genes have been described. Currently, testing is variable as there are no widely accepted guidelines for testing. This systematic review aimed to summarize the literature describing genetic changes and testing practices in childhood glaucoma. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) 2020 guidelines and registered with Prospero (ID CRD42023400467). A comprehensive review of Pubmed, Embase, and Cochrane databases was performed from inception through March 2, 2023 using the search terms: (glaucoma) AND (pediatric OR childhood OR congenital OR child OR infant OR infantile) AND (gene OR genetic OR genotype OR locus OR genomic OR mutation OR variant OR test OR screen OR panel). Information was extracted regarding genetic variants including genotype-phenotype correlation. Risk of bias was assessed using the Newcastle-Ottawa Scale. Of 1,916 records screened, 196 studies met inclusion criteria and 53 genes were discussed. Among study populations, mean age±SD at glaucoma diagnosis was 8.94±9.54 years and 50.4% were male. The most common gene discussed was CYP1B1, evaluated in 109 (55.6%) studies. CYP1B1 variants were associated with region and population-specific prevalence ranging from 5% to 86% among those with primary congenital glaucoma. MYOC variants were discussed in 31 (15.8%) studies with prevalence up to 36% among patients with juvenile open angle glaucoma. FOXC1 variants were discussed in 25 (12.8%) studies, which demonstrated phenotypic severity dependent on degree of gene expression and type of mutation. Overall risk of bias was low; the most common domains of bias were selection and comparability. Numerous genes and genetic changes have been associated with childhood glaucoma. Understanding the most common genes as well as potential genotype-phenotype correlation has the potential to improve diagnostic and prognostic outcomes for children with glaucoma.
Topics: Adolescent; Child; Female; Humans; Infant; Male; Genotype; Glaucoma; Glaucoma, Open-Angle; Mutation; Pedigree
PubMed: 38386645
DOI: 10.1371/journal.pone.0298883 -
JAMA Neurology Jul 2020Genetic and environmental factors are thought to contribute to cluster headache, and cluster headache can affect multiple members of a family. A thorough understanding...
IMPORTANCE
Genetic and environmental factors are thought to contribute to cluster headache, and cluster headache can affect multiple members of a family. A thorough understanding of its inheritance is critical to understanding the pathogenesis of this debilitating disease.
OBJECTIVE
To systematically review family history rates and inheritance patterns of cluster headache.
EVIDENCE REVIEW
A systematic review was performed in PubMed, Embase, and Cochrane Library. Search criteria were created by a librarian. Articles published between 1985 and 2016, after the publication date of a large review in 1985, were analyzed independently by 2 neurologists to identify family history rates and pedigrees. Pedigrees were analyzed by a genetic counselor.
FINDINGS
A total of 1995 studies were found (1988 through the search criteria and 7 through other means). Forty articles met inclusion criteria: 22 large cohort studies, 1 twin-based study, and 17 case reports or small case series. Across the 22 large cohort studies, the positive family history rate of cluster headache varied between 0% and 22%, with a median of 8.2%. The largest 5 studies, of 1134, 785, 693, 609, and 500 probands each, had a positive family history in 18.0% (numerator not provided), 5.1% (40 of 785 cases), 10.0% (numerator not provided), 2.0% (12 of 609 cases), and 11.2% (56 of 500 cases), respectively. No meta-analysis was performed, given differences in methodologies. Separately, 1 twin-based study examined 37 twin pairs and reported a concordance rate of 5.4% (2 pairs). Finally, 67 pedigrees were identified. Most pedigrees (46 of 67 [69%]) were consistent with an autosomal dominant pattern, but 19 of 67 (28%) were consistent with an autosomal recessive inheritance pattern; 10 pedigrees of probable or atypical cluster headache were identified, and all were consistent with an autosomal dominant inheritance pattern. The sex ratio for cluster headache in identified pedigrees was 1.39 (103:74) in affected men and boys compared with affected women and girls, which is lower than that of the general cluster headache population.
CONCLUSIONS AND RELEVANCE
Cluster headache is an inherited disorder in a subset of families and is associated with multiple hereditary patterns. There is an unexpectedly high preponderance of women and girls with familial cluster headache; genetic subanalyses limited to female participants are necessary to further explore this observation, because these data are otherwise masked by the higher numbers of male participants with cluster headache. Overall, this systematic review supports the notion that familial cluster headache is likely the result of multiple susceptibility genes as well as environmental factors.
Topics: Cluster Headache; Female; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Male; Pedigree
PubMed: 32310255
DOI: 10.1001/jamaneurol.2020.0682 -
Frontiers in Genetics 2023Whether human sexuality is the result of nature or nurture (or their complex interplay) represents a hot, often ideologically driven, and highly polarized debate with...
Whether human sexuality is the result of nature or nurture (or their complex interplay) represents a hot, often ideologically driven, and highly polarized debate with political and social ramifications, and with varying, conflicting findings reported in the literature. A number of heritability and behavioral genetics studies, including pedigree-based investigations, have hypothesized inheritance patterns of human sexual behaviors. On the other hand, in most twin, adoption, and nuclear family studies, it was not possible to disentangle between underlying genetic and shared environmental sources. Furthermore, these studies were not able to estimate the precise extent of genetic loading and to shed light both on the number and nature of the putative inherited factors, which remained largely unknown. Molecular genetic studies offer an unprecedented opportunity to overcome these drawbacks, by dissecting the molecular basis of human sexuality and allowing a better understanding of its biological roots if any. However, there exists no systematic review of the molecular genetics of human sexuality. Therefore, we undertook this critical systematic review and appraisal of the literature, with the ambitious aims of filling in these gaps of knowledge, especially from the methodological standpoint, and providing guidance to future studies. Sixteen studies were finally retained and overviewed in the present systematic review study. Seven studies were linkage studies, four studies utilized the candidate gene approach, and five studies were GWAS investigations. Limitations of these studies and implications for further research are discussed.
PubMed: 37693319
DOI: 10.3389/fgene.2023.1184758 -
Clinical Neurology and Neurosurgery Nov 2020Despite numerous reports in syndromic gliomas, the underlying genetic and molecular basis of familial, non-syndromic gliomas, in first degree relatives, remains unclear.... (Review)
Review
OBJECTIVE
Despite numerous reports in syndromic gliomas, the underlying genetic and molecular basis of familial, non-syndromic gliomas, in first degree relatives, remains unclear. This rare cohort of patients harboring invasive primary brain tumors with poor prognosis may provide a potential substrate of understanding the complex genetic cascade triggering tumorigenesis.
METHODS
A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) 2015 and The Cochrane Handbook of Systematic Reviews of Interventions. PubMed/MEDLINE, Embase and CENTRAL databases were accessed with set inclusion and exclusion criteria.
RESULTS
Following returns of 6756 articles, systematic analysis resulted in 48 papers, with 18 case series, 4 linkage analysis, 3 case-control studies, 1 cohort study, and 22 case reports. A total of 164 first degree relatives of 72 families were analyzed. The most common genetic alterations associated with non-syndromic familial gliomas reported to affect chromosomes 17 (51.1 % germline and 9.3 % tumor mutations), 22 (15.6 % germline and 6 % tumor mutations) and 1 and 19 (4.4 % germline and 9.3 % tumor mutations), with the most commonly affected genes TP53 (8.5 %) and NF2 (3.7 %). Tumor suppressors or cell-cycle regulators, cell signaling and transcription regulation or methylation were the most common gene function categories.
CONCLUSION
Four specific chromosomes (17, 22, 1 and 19) and two specific genes (TP53 and NF2) appear to be most commonly involved. This appears to be the first systematic review of genetic factors underlying non-syndromic glioma clustering in families. The defined list of genetic abnormalities, linked to familial gliomas, may facilitate therapeutic targets and future treatment design.
Topics: Brain Neoplasms; Case-Control Studies; Cell Transformation, Neoplastic; Cohort Studies; Glioma; Humans; Mutation; Pedigree
PubMed: 33039851
DOI: 10.1016/j.clineuro.2020.106222