Objective Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy. Methods We used a multi‐gene next‐generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy‐related genes in 9769 individuals. Clinical variant interpretation was performed using a semi‐quantitative scoring system based on existing professional practice guidelines. Results Molecular genetic testing provided a diagnosis in 14.9%‐24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single‐nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications. Significance Using an NGS gene panel with key high‐yield genes and robust analytic sensitivity as a first‐tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy.
Original research article INTRODUCTIONSignificant advances in copy-number detection have broadened the mutation spectrum for many clinical genetic disorders. 1,2 Intragenic deletion mutations are of considerable frequency in many disease genes, such as PAX6, CDKL5, and STXPB1. Recurrent rearrangements between segmentally duplicated sequences are also associated with a number of syndromic disorders. 3 For these known disorders, targeted gene testing by multiplex ligation-dependent amplification or exon-focused arrays has been useful. With the increasing uptake of exome sequencing into the clinical diagnostic approach, the need for testing previously uncharacterized genes for pathogenic copynumber variation (CNV) is a significant consideration, not only to detect aberrations in genes that may cause disease when haplo-insufficient but also in genes associated with recessive disorders for which the mutation has been identified in only one of the alleles by exome sequencing. 4 Whereas exome sequencing is still gaining popularity as a powerful clinical tool, whole-genome chromosomal microarray analysis (CMA) has become an indispensable screening method that is now routinely used as a first-tier test for children with intellectual disability, developmental delay, or congenital anomalies. 5 In less than 10 years, the CMA designs have evolved from low-resolution arrays containing large bacterial artificial chromosome clones or <100,000 oligonucleotide probes to high-resolution versions with more than 1 million probes. 6 As a result, several groups have identified single-gene pathogenic aberrations that boost the analytical sensitivity of CMA. 7 However, although some of these more recent arrays have higher density at disease genes, they do not all cover every exon in those genes and are therefore not capable of detecting some pathogenic intragenic mutations. Separately, data from exon-focused arrays have shown that up to 40% of intragenic mutations can involve just one or two exons within a gene, and therefore it is essential to cover all exons within targeted genes. 1 Copy-number detection in clinical genetic testing eventually will occur entirely through examination of next-generation data, whereas array comparative genomic hybridization (aCGH) and other assays will serve as complementary and confirmatory methods. 8 To complement whole-exome sequencing (WES) or whole-genome sequencing data in a meaningful way, an array with coverage of virtually all exons is essential. Until the time that WES/whole-genome sequencing can be used routinely and reliably for copy-number detection, a whole-exome array can be used as the ultimate whole-genome CMA platform. Purpose: Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its ut...
Characterization of genetic admixture of populations in the Americas and the Caribbean is of interest for anthropological, epidemiological, and historical reasons. Asthma has a higher prevalence and is more severe in populations with a high African component. Association of African ancestry with asthma has been demonstrated. We estimated admixture proportions of samples from six trihybrid populations of African descent and determined the relationship between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 237 ancestry informative markers in asthmatics and nonasthmatic controls from Barbados (190/277), Jamaica (177/529), Brazil (40/220), Colombia (508/625), African Americans from New York (207/171), and African Americans from Baltimore/Washington, D.C. (625/757). We estimated individual ancestries and evaluated genetic stratification using Structure and principal component analysis. Association of African ancestry and asthma and tIgE was evaluated by regression analysis. Mean SD African ancestry ranged from 0.76 ± 0.10 among Barbadians to 0.33 ± 0.13 in Colombians. The European component varied from 0.14 ± 0.05 among Jamaicans and Barbadians to 0.26 ± 0.08 among Colombians. African ancestry was associated with risk for asthma in Colombians (odds ratio (OR) = 4.5, P = 0.001) Brazilians (OR = 136.5, P = 0.003), and African Americans of New York (OR: 4.7; P = 0.040). African ancestry was also associated with higher tIgE levels among Colombians (β = 1.3, P = 0.04), Barbadians (β = 3.8, P = 0.03), and Brazilians (β = 1.6, P = 0.03). Our findings indicate that African ancestry can account for, at least in part, the association between asthma and its associated trait, tIgE levels.
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