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1.
Gene ; 854: 147108, 2023 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-36535464

RESUMO

BACKGROUND: Preeclampsia (PE) is an idiopathic disorder of pregnancy. The exact cause of PE remains unknown. Emerging evidence indicates that the cause of PE is linked to genetic factors. Therefore, the aim of this study was to identify the susceptibility genes for PE. METHODS: Nine families with severe PE were recruited. The whole-exome sequencing (WES) was performed on each family, and Sanger sequencing was used to identify the potential pathogenic genetic variants. RESULTS: After a rigorous bioinformatics analysis, compound heterozygous variants in the NPFFR2 gene, NM_004885.2: c.601A > G, p.Met201Val and c.995C > T, p.Ala332Val were found in the No.4 pedigree. Bioinformatics analysis showed that these sites were highly conserved among several species and were predicted to be pathogenic variants according to multiple online mutational function prediction software packages. Due to the compound heterozygous variants of NPFFR2, more bonds are generated between mutant amino acids and spatial adjacent amino acids, which may lead to more stable active conformation of protein and not easy to be degraded. CONCLUSIONS: We demonstrated for the first time that compound heterozygous variants of the NPFFR2 gene might be potentially associated with severe PE, the results of this study provide clinicians and researchers with a better understanding of the molecular mechanisms underlying severe PE in pregnant women.


Assuntos
Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Pré-Eclâmpsia/genética , Exoma , Mutação , Linhagem
2.
JAMA ; 329(1): 85-86, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36525251

RESUMO

This JAMA Insights discusses RNA sequencing, which allows detection of qualitative and quantitative changes in RNA expression across the genome in clinical samples, and how it may improve molecular diagnostic rates achieved by diagnostic exome sequencing and whole-genome sequencing alone.


Assuntos
Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Sequência de Bases , Análise de Sequência de RNA
3.
Bioinformatics ; 39(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36484701

RESUMO

SUMMARY: Whole-exome and targeted sequencing are widely utilized both in translational cancer genomics and in the setting of precision medicine. The benchmarking of computational methods and tools that are in continuous development is fundamental for the correct interpretation of somatic genomic profiling results. To this aim we developed synggen, a tool for the fast generation of large-scale realistic and heterogeneous cancer whole-exome and targeted sequencing synthetic datasets, which enables the incorporation of phased germline single nucleotide polymorphisms and complex allele-specific somatic genomic events. Synggen performances and effectiveness in generating synthetic cancer data are shown across different scenarios and considering different platforms with distinct characteristics. AVAILABILITY AND IMPLEMENTATION: synggen is freely available at https://bitbucket.org/CibioBCG/synggen/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Software , Genômica/métodos , Exoma , Neoplasias/genética
5.
Sci Rep ; 12(1): 21028, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36470944

RESUMO

The mutational spectrum of asthma and allergy associated genes is not known although recent biobank based exome sequencing studies included these traits. We therefore conducted a secondary analysis of exome data from 281,104 UK Biobank samples for association of mostly rare variants with asthma, allergic rhinitis and atopic dermatitis. Variants of interest (VOI) were tabulated, shared genes annotated and compared to earlier genome-wide SNP association studies (GWAS), whole genome sequencing, exome and bisulfit sequencing studies. 354 VOI were significantly associated with asthma, allergic rhinitis and atopic dermatitis. They cluster mainly in two large regions on chromosome 6 and 17. After exclusion of the variants associated with atopic dermatitis and redundant variants, 321 unique VOI remain in 122 unique genes. 30 genes are shared among the 87 genes with increased and the 65 genes with decreased risk for allergic disease. 85% of genes identified earlier by common GWAS SNPs are not replicated here. Most identified genes are located in interferon É£ and IL33 signaling pathway. These genes include already known but also new pharmacological targets, including the IL33 receptor ST2/IL1RL1, as well as TLR1, ALOX15, GSDMA, BTNL2, IL13 and IKZF3. Future pharmacological studies will need to included these VOI for stratification of the study population paving the way to individualized treatment.


Assuntos
Asma , Dermatite Atópica , Rinite Alérgica , Humanos , Dermatite Atópica/genética , Dermatite Atópica/epidemiologia , Exoma/genética , Interleucina-33/genética , Asma/genética , Asma/epidemiologia , Estudo de Associação Genômica Ampla , Rinite Alérgica/genética , Predisposição Genética para Doença , Butirofilinas/genética , Proteínas de Neoplasias/genética
6.
Hum Genomics ; 16(1): 71, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36539902

RESUMO

BACKGROUND: Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia, the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity among large tribal pedigrees. RESULTS: We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known epilepsy-related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline-based variant prioritization approach in an attempt to discover putative causative variants. We identified 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity was observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. CONCLUSION: Several putative pathogenic variants in known epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci which may be prioritized for further investigation.


Assuntos
Epilepsia , Exoma , Humanos , Arábia Saudita/epidemiologia , Exoma/genética , Epilepsia/epidemiologia , Epilepsia/genética , Epilepsia/diagnóstico , Linhagem , Predisposição Genética para Doença
7.
Cell Rep Med ; 3(12): 100855, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36513072

RESUMO

Nonalcoholic fatty liver disease is common and highly heritable. Genetic studies of hepatic fat have not sufficiently addressed non-European and rare variants. In a medical biobank, we quantitate hepatic fat from clinical computed tomography (CT) scans via deep learning in 10,283 participants with whole-exome sequences available. We conduct exome-wide associations of single variants and rare predicted loss-of-function (pLOF) variants with CT-based hepatic fat and perform cross-modality replication in the UK Biobank (UKB) by linking whole-exome sequences to MRI-based hepatic fat. We confirm single variants previously associated with hepatic fat and identify several additional variants, including two (FGD5 H600Y and CITED2 S198_G199del) that replicated in UKB. A burden of rare pLOF variants in LMF2 is associated with increased hepatic fat and replicates in UKB. Quantitative phenotypes generated from clinical imaging studies and intersected with genomic data in medical biobanks have the potential to identify molecular pathways associated with human traits and disease.


Assuntos
Exoma , Hepatopatia Gordurosa não Alcoólica , Humanos , Exoma/genética , Bancos de Espécimes Biológicos , Fenótipo , Tomografia Computadorizada por Raios X , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/genética , Proteínas Repressoras/genética , Transativadores/genética
8.
Genes (Basel) ; 13(12)2022 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-36553485

RESUMO

Neurological phenotypes such as intellectual disability occur in almost half of patients with neurofibromatosis 1 (NF1). Current genotype-phenotype studies have failed to reveal the mechanism underlying this clinical variability. Despite the presence of pathogenic variants of NF1, modifier genes likely determine the occurrence and severity of neurological phenotypes. Exome sequencing data were used to identify genetic variants in 13 NF1 patients and 457 healthy controls, and this information was used to identify candidate modifier genes underlying neurological phenotypes based on an optimal sequence kernel association test. Thirty-six genes were identified as significant modifying factors in patients with neurological phenotypes and all are highly expressed in the nervous system. A review of the literature confirmed that 19 genes including CUL7, DPH1, and BCO1 are clearly associated with the alteration of neurological functioning and development. Our study revealed the enrichment of rare variants of 19 genes closely related to neurological development and functioning in NF1 patients with neurological phenotypes, indicating possible modifier genes and variants affecting neurodevelopment. Further studies on rare genetic variants of candidate modifier genes may help explain the clinical heterogeneity of NF1.


Assuntos
Neurofibromatose 1 , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Genes Modificadores , Fenótipo , Exoma
9.
Genes (Basel) ; 13(12)2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-36553572

RESUMO

Routine diagnostics is biased towards genes and variants with satisfactory evidence, but rare disorders with only little confirmation of their pathogenicity might be missed. Many of these genes can, however, be considered relevant, although they may have less evidence because they lack OMIM entries or comprise only a small number of publicly available variants from one or a few studies. Here, we present 89 individuals harbouring variants in 77 genes for which only a small amount of public evidence on their clinical significance is available but which we still found to be relevant enough to be reported in routine diagnostics. For 21 genes, we present case reports that confirm the lack or provisionality of OMIM associations (ATP6V0A1, CNTN2, GABRD, NCKAP1, RHEB, TCF7L2), broaden the phenotypic spectrum (CC2D1A, KCTD17, YAP1) or substantially strengthen the confirmation of genes with limited evidence in the medical literature (ADARB1, AP2M1, BCKDK, BCORL1, CARS2, FBXO38, GABRB1, KAT8, PRKD1, RAB11B, RUSC2, ZNF142). Routine diagnostics can provide valuable information on disease associations and support for genes without requiring tremendous research efforts. Thus, our results validate and delineate gene-disorder associations with the aim of motivating clinicians and scientists in diagnostic departments to provide additional evidence via publicly available databases or by publishing short case reports.


Assuntos
Transtornos do Neurodesenvolvimento , Humanos , Transtornos do Neurodesenvolvimento/genética , Exoma
10.
Exp Mol Med ; 54(11): 1862-1871, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36323850

RESUMO

Despite substantial advances in disease genetics, studies to date have largely focused on individuals of European descent. This limits further discoveries of novel functional genetic variants in other ethnic groups. To alleviate the paucity of East Asian population genome resources, we established the Korean Variant Archive 2 (KOVA 2), which is composed of 1896 whole-genome sequences and 3409 whole-exome sequences from healthy individuals of Korean ethnicity. This is the largest genome database from the ethnic Korean population to date, surpassing the 1909 Korean individuals deposited in gnomAD. The variants in KOVA 2 displayed all the known genetic features of those from previous genome databases, and we compiled data from Korean-specific runs of homozygosity, positively selected intervals, and structural variants. In doing so, we found loci, such as the loci of ADH1A/1B and UHRF1BP1, that are strongly selected in the Korean population relative to other East Asian populations. Our analysis of allele ages revealed a correlation between variant functionality and evolutionary age. The data can be browsed and downloaded from a public website ( https://www.kobic.re.kr/kova/ ). We anticipate that KOVA 2 will serve as a valuable resource for genetic studies involving East Asian populations.


Assuntos
Exoma , Humanos , República da Coreia , Polimorfismo de Nucleotídeo Único
11.
Am J Hum Genet ; 109(11): 1947-1959, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36332610

RESUMO

The past decade has witnessed a rapid evolution in rare disease (RD) research, fueled by the availability of genome-wide (exome and genome) sequencing. In 2011, as this transformative technology was introduced to the research community, the Care4Rare Canada Consortium was launched: initially as FORGE, followed by Care4Rare, and Care4Rare SOLVE. Over what amounted to three eras of diagnosis and discovery, the Care4Rare Consortium used exome sequencing and, more recently, genome and other 'omic technologies to identify the molecular cause of unsolved RDs. We achieved a diagnostic yield of 34% (623/1,806 of participating families), including the discovery of deleterious variants in 121 genes not previously associated with disease, and we continue to study candidate variants in novel genes for 145 families. The Consortium has made significant contributions to RD research, including development of platforms for data collection and sharing and instigating a Canadian network to catalyze functional characterization research of novel genes. The Consortium was instrumental to implementing genome-wide sequencing as a publicly funded test for RD diagnosis in Canada. Despite the successes of the past decade, the challenge of solving all RDs remains enormous, and the work is far from over. We must leverage clinical and 'omic data for secondary use, develop tools and policies to support safe data sharing, continue to explore the utility of new and emerging technologies, and optimize research protocols to delineate complex disease mechanisms. Successful approaches in each of these realms is required to offer diagnostic clarity to all families with RDs.


Assuntos
Exoma , Doenças Raras , Humanos , Doenças Raras/diagnóstico , Doenças Raras/genética , Canadá , Exoma/genética , Estudos de Associação Genética
12.
J Cell Mol Med ; 26(23): 5901-5916, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36380727

RESUMO

The transformation biology of secondary acute myeloid leukaemia (AML) from myelodysplastic syndromes (MDSs) is still not fully understood. We performed paired self-controlled sequencing, including targeted, whole exome, and single-cell RNA sequencing, in a cohort of MDS patients to search for AML transformation-related mutations (TRMs). Thirty-nine target genes from paired samples from 72 patients with MDS who had undergone AML transformation were analysed. The targeted sequencing results showed that 64 of 72 (88.9%) patients presented TRMs involving signalling pathway activation, transcription factors, or tumour suppressors. Of the 64 patients, most of the TRMs (62.5%, 40 cases) emerged at the leukaemia transformation point. Paired whole exome sequencing showed some presumptive TRMs, which were not included in the reference targets in three patients. No patient developed AML only by acquiring mutations involved in epigenetic modulation or ribonucleic acid splicing. Single-cell sequencing indicated that the activating cell signalling route was related to TRMs in one paired sample. Targeted sequencing defined TRMs were limited to a small set of seven genes (in the order: NRAS/KRAS, CEBPA, TP53, FLT3, CBL, PTPN11, and RUNX1, accounting for nearly 90.0% of the TRMs). In conclusion, somatic mutations involved in signalling, transcription factors, or tumour suppressors appeared to be a precondition for AML transformation from MDS.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Leucemia Mieloide Aguda/genética , Mutação/genética , Exoma/genética , Regulação da Expressão Gênica
13.
BMC Bioinformatics ; 23(1): 496, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401182

RESUMO

Classification of different cancer types is an essential step in designing a decision support model for early cancer predictions. Using various machine learning (ML) techniques with ensemble learning is one such method used for classifications. In the present study, various ML algorithms were explored on twenty exome datasets, belonging to 5 cancer types. Initially, a data clean-up was carried out on 4181 variants of cancer with 88 features, and a derivative dataset was obtained using natural language processing and probabilistic distribution. An exploratory dataset analysis using principal component analysis was then performed in 1 and 2D axes to reduce the high-dimensionality of the data. To significantly reduce the imbalance in the derivative dataset, oversampling was carried out using SMOTE. Further, classification algorithms such as K-nearest neighbour and support vector machine were used initially on the oversampled dataset. A 4-layer artificial neural network model with 1D batch normalization was also designed to improve the model accuracy. Ensemble ML techniques such as bagging along with using KNN, SVM and MLPs as base classifiers to improve the weighted average performance metrics of the model. However, due to small sample size, model improvement was challenging. Therefore, a novel method to augment the sample size using generative adversarial network (GAN) and triplet based variational auto encoder (TVAE) was employed that reconstructed the features and labels generating the data. The results showed that from initial scrutiny, KNN showed a weighted average of 0.74 and SVM 0.76. Oversampling ensured that the accuracy of the derivative dataset improved significantly and the ensemble classifier augmented the accuracy to 82.91%, when the data was divided into 70:15:15 ratio (training, test and holdout datasets). The overall evaluation metric value when GAN and TVAE increased the sample size was found to be 0.92 with an overall comparison model of 0.66. Therefore, the present study designed an effective model for classifying cancers which when implemented to real world samples, will play a major role in early cancer diagnosis.


Assuntos
Exoma , Neoplasias , Humanos , Exoma/genética , Detecção Precoce de Câncer , Aprendizado de Máquina , Algoritmos , Neoplasias/diagnóstico , Neoplasias/genética
14.
Genome Med ; 14(1): 131, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36414972

RESUMO

BACKGROUND: The uptake of exome/genome sequencing has introduced unexpected testing results (incidental findings) that have become a major challenge for both testing laboratories and providers. While the American College of Medical Genetics and Genomics has outlined guidelines for laboratory management of clinically actionable secondary findings, debate remains as to whether incidental findings should be returned to patients, especially those representing pediatric populations. METHODS: The Sequencing Analysis and Diagnostic Yield working group in the Clinical Sequencing Evidence-Generating Research Consortium has collected a cohort of pediatric patients found to harbor a genomic sequencing-identified non-ACMG-recommended incidental finding. The incidental variants were not thought to be associated with the indication for testing and were disclosed to patients and families. RESULTS: In total, 23 "non-ACMG-recommended incidental findings were identified in 21 pediatric patients included in the study. These findings span four different research studies/laboratories and demonstrate differences in incidental finding return rate across study sites. We summarize specific cases to highlight core considerations that surround identification and return of incidental findings (uncertainty of disease onset, disease severity, age of onset, clinical actionability, and personal utility), and suggest that interpretation of incidental findings in pediatric patients can be difficult given evolving phenotypes. Furthermore, return of incidental findings can benefit patients and providers, but do present challenges. CONCLUSIONS: While there may be considerable benefit to return of incidental genetic findings, these findings can be burdensome to providers and present risk to patients. It is important that laboratories conducting genomic testing establish internal guidelines in anticipation of detection. Moreover, cross-laboratory guidelines may aid in reducing the potential for policy heterogeneity across laboratories as it relates to incidental finding detection and return. However, future discussion is required to determine whether cohesive guidelines or policy statements are warranted.


Assuntos
Exoma , Genoma Humano , Humanos , Estados Unidos , Mapeamento Cromossômico , Sequência de Bases , Genômica
15.
PLoS One ; 17(11): e0277680, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36395175

RESUMO

The UK Biobank genotyped about 500k participants using Applied Biosystems Axiom microarrays. Participants were subsequently sequenced by the UK Biobank Exome Sequencing Consortium. Axiom genotyping was highly accurate in comparison to sequencing results, for almost 100,000 variants both directly genotyped on the UK Biobank Axiom array and via whole exome sequencing. However, in a study using the exome sequencing results of the first 50k individuals as reference (truth), it was observed that the positive predictive value (PPV) decreased along with the number of heterozygous array calls per variant. We developed a novel addition to the genotyping algorithm, Rare Heterozygous Adjusted (RHA), to significantly improve PPV in variants with minor allele frequency below 0.01%. The improvement in PPV was roughly equal when comparing to the exome sequencing of 50k individuals, or to the more recent ~200k individuals. Sensitivity was higher in the 200k data. The improved calling algorithm, along with enhanced quality control of array probesets, significantly improved the positive predictive value and the sensitivity of array data, making it suitable for the detection of ultra-rare variants.


Assuntos
Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Estudos Retrospectivos , Bancos de Espécimes Biológicos , Polimorfismo de Nucleotídeo Único , Algoritmos , Reino Unido
16.
Genome Biol ; 23(1): 241, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376909

RESUMO

Aneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as the infinite sites assumption, allowing multiple mutations and parallel evolution, and does not treat adjacent loci as independent, allowing overlapping copy-number events. Using simulations and multiple data types from 2780 tumors, we use MEDICC2 to demonstrate accurate inference of phylogenies, clonal and subclonal WGD, and ancestral copy-number states.


Assuntos
Neoplasias , Humanos , Filogenia , Neoplasias/genética , Neoplasias/patologia , Variações do Número de Cópias de DNA , Exoma , Genoma Humano
17.
Proc Natl Acad Sci U S A ; 119(46): e2203491119, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36350923

RESUMO

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (P < 3.64e-7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense (n = 41) or truncating (n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (DDX3X, MECP2, WDR45, and HDAC8). This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Criança , Masculino , Feminino , Humanos , Transtorno Autístico/genética , Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Exoma , Histona Desacetilases/genética , Proteínas Repressoras/genética , Proteínas de Transporte/genética
18.
Sci Rep ; 12(1): 19209, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357507

RESUMO

Nowadays, exome sequencing is a robust and cost-efficient genetic diagnostic tool already implemented in many clinical laboratories. Despite it has undoubtedly improved our diagnostic capacity and has allowed the discovery of many new Mendelian-disease genes, it only provides a molecular diagnosis in up to 25-30% of cases. Here, we comprehensively evaluate the results of a large sample set of 4974 clinical exomes performed in our laboratory over a period of 5 years, showing a global diagnostic rate of 24.62% (1391/4974). For the evaluation we establish different groups of diseases and demonstrate how the diagnostic rate is not only dependent on the analyzed group of diseases (43.12% in ophthalmological cases vs 16.61% in neurological cases) but on the specific disorder (47.49% in retinal dystrophies vs 24.02% in optic atrophy; 18.88% in neuropathies/paraparesias vs 11.43% in dementias). We also detail the most frequent mutated genes within each group of disorders and discuss, on our experience, further investigations and directions needed for the benefit of patients.


Assuntos
Atrofia Óptica , Distrofias Retinianas , Humanos , Exoma/genética , Distrofias Retinianas/genética , Atrofia Óptica/genética
19.
BMC Med Genomics ; 15(1): 237, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357908

RESUMO

BACKGROUND: Childhood hearing impairment (HI) is genetically heterogeneous with many implicated genes, however, only a few of these genes are reported in African populations. METHODS: This study used exome and Sanger sequencing to resolve the possible genetic cause of non-syndromic HI in a Ghanaian family. RESULTS: We identified a novel variant c.3041G > A: p.(Gly1014Glu) in GREB1L (DFNA80) in the index case. The GREB1L: p.(Gly1014Glu) variant had a CADD score of 26.5 and was absent from human genomic databases such as TopMed and gnomAD. In silico homology protein modeling approaches displayed major structural differences between the wildtype and mutant proteins. Additionally, the variant was predicted to probably affect the secondary protein structure that may impact its function. Publicly available expression data shows a higher expression of Greb1L in the inner ear of mice during development and a reduced expression in adulthood, underscoring its importance in the development of the inner ear structures. CONCLUSION: This report on an African individual supports the association of GREB1L variant with non-syndromic HI and extended the evidence of the implication of GREB1L variants in HI in diverse populations.


Assuntos
Perda Auditiva , Camundongos , Humanos , Animais , Adulto , Criança , Gana , Perda Auditiva/genética , Exoma , Proteínas/genética , Linhagem , Mutação
20.
Hum Genomics ; 16(1): 55, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357925

RESUMO

BACKGROUND: Cardiomyopathies are a leading cause of progressive heart failure and sudden cardiac death; however, their genetic aetiology remains poorly understood. We hypothesised that variants in noncoding regulatory regions and oligogenic inheritance mechanisms may help close the diagnostic gap. METHODS: We first analysed whole-genome sequencing data of 143 parent-offspring trios from Genomics England 100,000 Genomes Project. We used gene panel testing and a phenotype-based, variant prioritisation framework called Exomiser to identify candidate genes in trios. To assess the contribution of noncoding DNVs to cardiomyopathies, we intersected DNVs with open chromatin sequences from single-cell ATAC-seq data of cardiomyocytes. We also performed a case-control analysis in an exome-negative cohort, including 843 probands and 19,467 controls, to assess the association between noncoding variants in known cardiomyopathy genes and disease. RESULTS: In the trio analysis, a definite or probable genetic diagnosis was identified in 21 probands according to the American College of Medical Genetics guidelines. We identified novel DNVs in diagnostic-grade genes (RYR2, TNNT2, PTPN11, MYH7, LZR1, NKX2-5), and five cases harbouring a combination of prioritised variants, suggesting that oligogenic inheritance and genetic modifiers contribute to cardiomyopathies. Phenotype-based ranking of candidate genes identified in noncoding DNV analysis revealed JPH2 as the top candidate. Moreover, a case-control analysis revealed an enrichment of rare noncoding variants in regulatory elements of cardiomyopathy genes (p = .035, OR = 1.43, 95% Cl = 1.095-1.767) versus controls. Of the 25 variants associated with disease  (p< 0.5), 23 are novel and nine are predicted to disrupt transcription factor binding motifs. CONCLUSION: Our results highlight complex genetic mechanisms in cardiomyopathies and reveal novel genes for future investigations.


Assuntos
Cardiomiopatias , Predisposição Genética para Doença , Humanos , Cardiomiopatias/genética , Exoma , Fenótipo , Sequências Reguladoras de Ácido Nucleico
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