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Journal of Current Ophthalmology 2023To look for causative genetic mutations in a series of Iranian families with strabismus. In addition, we systematically reviewed all the published articles regarding the... (Review)
Review
Role of Abelson Helper Integration Site 1, Nebulin, and Paired Box 3 Genes in the Development of Nonsyndromic Strabismus in a Series of Iranian Families: Sequence Analysis and Systematic Review of the Genetics of Nonsyndromic Strabismus.
PURPOSE
To look for causative genetic mutations in a series of Iranian families with strabismus. In addition, we systematically reviewed all the published articles regarding the role of genetic variations in primary and nonsyndromic comitant strabismus.
METHODS
Four families with a history of multiple cases of primary and nonsyndromic comitant strabismus were enrolled in this study. Polymerase chain reaction and Sanger sequencing of exons 23, 11, and 3 of the Abelson helper integration site 1 (), nebulin (), and paired box 3 () genes were performed, respectively. One offspring of a consanguineous marriage underwent whole-exome sequencing (WES) to look for possible causative variants. To conduct a systematic review, we thoroughly searched PubMed, Scopus, and ISI Web of Knowledge extracting relevant publications, released by April 2021.
RESULTS
We examined four Iranian strabismus pedigrees with multiple affected offspring in different generations. Among these 17 participants, 10 family members had strabismus and 7 were healthy. Sanger sequencing did not reveal a causative mutation. Therefore, to further investigate, one affected offspring was chosen for WES. The WES study demonstrated two possible variants in and genes. These genetic variants showed high allele frequency in our population and are thought to be polymorphisms in our series of Iranian families.
CONCLUSIONS
We demonstrated that mutations in , , and genes were not common in a series of Iranian patients with familial strabismus. Moreover, by performing WES, we revealed that two variants of uncertain significance as possible causative variants for strabismus are not related to this disease in our population.
PubMed: 38681684
DOI: 10.4103/joco.joco_53_22 -
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 -
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 -
BMC Ophthalmology Feb 2024Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people...
BACKGROUND
Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people globally. This review is based on a retrospective analysis of research articles reporting IRDs associated genetic findings in Pakistani families between 1999 and April 2023.
METHODS
Articles were retrieved through survey of online sources, notably, PubMed, Google Scholar, and Web of Science. Following a stringent selection criterion, a total of 126 research articles and conference abstracts were considered. All reported variants were cross-checked and validated for their correct genomic nomenclature using different online resources/databases, and their pathogenicity scores were explained as per ACMG guidelines.
RESULTS
A total of 277 unique sequence variants in 87 distinct genes, previously known to cause IRDs, were uncovered. In around 70% cases, parents of the index patient were consanguineously married, and approximately 88.81% of the detected variants were found in a homozygous state. Overall, more than 95% of the IRDs cases were recessively inherited. Missense variants were predominant (41.88%), followed by Indels/frameshift (26.35%), nonsense (19.13%), splice site (12.27%) and synonymous change (0.36%). Non-syndromic IRDs were significantly higher than syndromic IRDs (77.32% vs. 22.68%). Retinitis pigmentosa (RP) was the most frequently observed IRD followed by Leber's congenital amaurosis (LCA). Altogether, mutations in PDE6A gene was the leading cause of IRDs in Pakistani families followed by mutations in TULP1 gene.
CONCLUSION
In summary, Pakistani families are notable in expressing recessively inherited monogenic disorders including IRDs likely due to the highest prevalence of consanguinity in the country that leads to expression of rare pathogenic variants in homozygous state.
Topics: Humans; Pakistan; Retrospective Studies; Retinal Dystrophies; Retina; Retinitis Pigmentosa; Mutation; Pedigree; Eye Proteins; Cyclic Nucleotide Phosphodiesterases, Type 6
PubMed: 38317096
DOI: 10.1186/s12886-024-03319-7 -
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 -
CNS Neuroscience & Therapeutics Mar 2024Mitochondrial complex III (CIII) deficiency is an autosomal recessive disease characterized by symptoms such as ataxia, cognitive dysfunction, and spastic paraplegia....
BACKGROUND
Mitochondrial complex III (CIII) deficiency is an autosomal recessive disease characterized by symptoms such as ataxia, cognitive dysfunction, and spastic paraplegia. Multiple genes are associated with complex III defects. Among them, the mutation of TTC19 is a rare subtype.
METHODS
We screened a Chinese boy with weakness of limbs and his non-consanguineous parents by whole exome sequencing and targeted sequencing.
RESULTS
We report a Chinese boy diagnosed with mitochondrial complex III defect type 2 carrying a homozygous variant (c.719-732del, p.Leu240Serfs*17) of the TTC19 gene. According to the genotype analysis of his family members, this is an autosomal recessive inheritance. We provide his clinical manifestation.
CONCLUSIONS
A new type of TTC19 mutation (c.719-732del, p.Leu240Serfs*17) was found, which enriched the TTC19 gene mutation spectrum and provided new data for elucidating the pathogenesis of CIII-deficient diseases.
Topics: Male; Humans; Electron Transport Complex III; Membrane Proteins; Mutation; Peripheral Nervous System Diseases; Movement Disorders; Pedigree; Mitochondrial Diseases
PubMed: 37927170
DOI: 10.1111/cns.14425 -
Oncology 2024The objective of this study was to reclassify published germline CDH1 variants identified in gastric cancer (GC) in accordance with the latest ClinVar definition and to...
INTRODUCTION
The objective of this study was to reclassify published germline CDH1 variants identified in gastric cancer (GC) in accordance with the latest ClinVar definition and to correlate their pathogenicity with the established international clinical criteria for genetic testing.
METHODS
The relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations in accord with PRISMA guidelines. The collected variants were classified according to the latest ClinVar definition into the following classes: benign (B), likely benign (LB), pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS). The McNemar test was used to compare the adequacy of current versus previous International GC Linkage Consortium (IGCLC) criteria.
RESULTS
We reclassified a total of 247 CDH1 variants, and we identified that about 70% of B/LB variant carriers were not fulfilling the defined clinical criteria. Instead, all P/LP variants (100%) were associated with the hereditary diffuse gastric cancer (HDGC) phenotype fulfilling the 2020 ILGCC criteria, with a significant improvement (p = 0.025) compared to previous version.
CONCLUSIONS
We conclude that germline CDH1 genetic testing is indicated only in families meeting the clinical criteria for the HDGC syndrome. This observation suggests that clinical phenotypes that do not clearly fulfill these criteria should not be considered for CDH1 genetic testing.
Topics: Humans; Genetic Predisposition to Disease; Stomach Neoplasms; Pedigree; Genetic Testing; Germ-Line Mutation; Cadherins; Adenocarcinoma; Antigens, CD
PubMed: 37725907
DOI: 10.1159/000533774 -
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 -
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