Dataset Information

Exome/Genome Sequencing in Undiagnosed Syndromes.

ABSTRACT: Exome sequencing (ES) and genome sequencing (GS) have radically transformed the diagnostic approach to undiagnosed rare/ultrarare Mendelian diseases. Next-generation sequencing (NGS), the technology integral for ES, GS, and most large (100+) gene panels, has enabled previously unimaginable diagnoses, changes in medical management, new treatments, and accurate reproductive risk assessments for patients, as well as new disease gene discoveries. Yet, challenges remain, as most individuals remain undiagnosed with current NGS. Improved NGS technology has resulted in long-read sequencing, which may resolve diagnoses in some patients who do not obtain a diagnosis with current short-read ES and GS, but its effectiveness is unclear, and it is expensive. Other challenges that persist include the resolution of variants of uncertain significance, the urgent need for patients with ultrarare disorders to have access to therapeutics, the need for equity in patient access to NGS-based testing, and the study of ethical concerns. However, the outlook for undiagnosed disease resolution is bright, due to continual advancements in the field.

SUBMITTER: Sullivan JA

PROVIDER: S-EPMC10483513 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Exome/Genome Sequencing in Undiagnosed Syndromes.

Sullivan Jennifer A JA Schoch Kelly K Spillmann Rebecca C RC Shashi Vandana V

Annual review of medicine 20230101

Exome sequencing (ES) and genome sequencing (GS) have radically transformed the diagnostic approach to undiagnosed rare/ultrarare Mendelian diseases. Next-generation sequencing (NGS), the technology integral for ES, GS, and most large (100+) gene panels, has enabled previously unimaginable diagnoses, changes in medical management, new treatments, and accurate reproductive risk assessments for patients, as well as new disease gene discoveries. Yet, challenges remain, as most individuals remain un ...[more]

PMID: 36706750

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Project description:ObjectiveNigeria, along with other Sub-Saharan African countries, bears the highest burden of epilepsy worldwide. This high prevalence is attributed to a combination of factors, including a significant incidence of infectious diseases, perinatal complications, and genetic etiologies. Genetic testing is rarely available and is not typically included in the routine diagnostic work-up for individuals with infantile and childhood epilepsy syndromes in these regions. Exome sequencing (ES) offers a diagnostic yield of 24%-62%, but these figures primarily reflect data from high-income countries (HICs) and may not be applicable to low- and middle-income countries (LMICs). In this study, we employed ES to investigate the genetic basis of early-onset epilepsy in 22 affected children from Nigeria.MethodsThe study involved sampling of patients diagnosed with early-onset epilepsy syndromes at the Lagos State University Teaching Hospital (LASUTH) Neurology clinic. Venous blood samples were collected, and genomic DNA was isolated and purified. Molecular analysis included DNA fragmentation, ligation, target enrichment, library preparation, and whole-exome sequencing. Computational analysis involved variant calling, curation, and classification using specialized tools and databases.ResultsPathogenic variants were identified in 6 out of 22 individuals, equaling a diagnostic yield of 27.3% and comprising variants in BPTF, NAA15, SCN1A, TUBA1A and twice in CACNA1A.SignificanceIn this study, we present the first exome study on early-onset epilepsy syndromes from West Africa, facilitated by a Nigerian-German research collaboration. Our findings reveal a genetic diagnostic yield comparable to that of HICs. The integration of genomic medicine into epilepsy management in Nigeria holds promising prospects for improving patient care and reducing mortality rates.Plain language summaryThis study represents the first published exome findings in Nigerian children with early-onset epilepsy, revealing a genetic diagnosis in 27% of cases. Pathogenic variants were identified in five genes amongst 6 of 22 patients, underscoring the potential of genetic testing to enhance epilepsy management in developing nations like Nigeria.

Dataset Information

Exome/Genome Sequencing in Undiagnosed Syndromes.

Publications

Exome/Genome Sequencing in Undiagnosed Syndromes.

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