Diagnostic Yield Of Exome Sequencing Research Articles

Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease.

Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels.

The cost and diagnostic yield of exome sequencing for children with suspected genetic disorders: a benchmarking study.

This study aimed to generate benchmark estimates for the cost, diagnostic yield, and cost per positive diagnosis of diagnostic exome sequencing (ES) in heterogeneous pediatric patient populations and to illustrate how the design of an ES service can influence its cost and yield. A literature review and Monte Carlo simulations were used to generate benchmark estimates for singleton and trio ES. A cost model for the Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study, which is testing a proposed delivery model for diagnostic ES in British Columbia, is used to illustrate the potential effects of changing the service design. The benchmark diagnostic yield was 34.3% (95% confidence interval (CI): 23.2-46.5) for trio ES and 26.5% (95% CI: 12.9-42.9) for singleton ES. The benchmark cost of delivery was C$6,437 (95% CI: $5,305-$7,704) in 2016 Canadian dollars (US$4,859; 4,391€) for trio ES and C$2,576 (95% CI: $1,993-$3,270) (US$1,944; 1,757€) for singleton ES. Scenario models for CAUSES suggest that alternative service designs could reduce costs but might lead to a higher cost per diagnosis due to lower yields. Broad conclusions about the cost-effectiveness of ES should be drawn with caution when relying on studies that use cost or yield assumptions that lie at the extremes of the benchmark ranges.

Comprehensive use of extended exome analysis improves diagnostic yield in rare disease: a retrospective survey in 1,059 cases

PurposeWe sought to determine the analytical sensitivity of several extended exome variation analysis approaches in terms of their contribution to diagnostic yield and their clinical feasibility.MethodsWe retrospectively analyzed the results of genetic testing in 1,059 distinct cases referred for exome sequencing to our institution. In these, we routinely employed extended exome analysis approaches in addition to basic variant analysis, including (i) copy-number variation (CNV) detection, (ii) nonconsensus splice defect detection, (ii) genomic breakpoint detection, (iv) homozygosity mapping, and (v) mitochondrial variant analysis.ResultsExtended exome analysis approaches assisted in identification of causative genetic variant in 44 cases, which represented a 4.2% increase in diagnostic yield. The greatest contribution was associated with CNV analysis (1.8%) and splice variant prediction (1.2%), and the remaining approaches contributed an additional 1.2%. Analysis of workload has shown that on average nine additional variants per case had to be interpreted in the extended analysis.ConclusionWe show that extended exome analysis approaches improve the diagnostic yield of heterogeneous genetic disorders and result in considerable increase of diagnostic yield of exome sequencing with a minor increase of interpretative workload.

Outcomes of Diagnostic Exome Sequencing in Patients With Diagnosed or Suspected Autism Spectrum Disorders

BackgroundExome sequencing has recently been proved to be a successful diagnostic method for complex neurodevelopmental disorders. However, the diagnostic yield of exome sequencing for autism spectrum disorders has not been extensively evaluated in large cohorts to date. Materials and MethodsWe performed diagnostic exome sequencing in a cohort of 163 individuals with autism spectrum disorder (66.3%) or autistic features (33.7%). ResultsThe diagnostic yield observed in patients in our cohort was 25.8% (42 of 163) for positive or likely positive findings in characterized disease genes, while a candidate genetic etiology was reported for an additional 3.3% (4 of 120) of patients. Among the positive findings in the patients with autism spectrum disorder or autistic features, 61.9% were the result of de novo mutations. Patients presenting with psychiatric conditions or ataxia or paraplegia in addition to autism spectrum disorder or autistic features were significantly more likely to receive positive results compared with patients without these clinical features (95.6% vs 27.1%, P < 0.0001; 83.3% vs 21.2%, P < 0.0001, respectively). The majority of the positive findings were in recently identified autism spectrum disorder genes, supporting the importance of diagnostic exome sequencing for patients with autism spectrum disorder or autistic features as the causative genes might evade traditional sequential or panel testing. ConclusionsThese results suggest that diagnostic exome sequencing would be an efficient primary diagnostic method for patients with autism spectrum disorders or autistic features. Moreover, our data may aid clinicians to better determine which subset of patients with autism spectrum disorder with additional clinical features would benefit the most from diagnostic exome sequencing.

Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]). Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.

Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers.

Clinical exome sequencing is nondiagnostic for about 75% of patients evaluated for a possible Mendelian disorder. We examined the ability of systematic reevaluation of exome data to establish additional diagnoses. The exome and phenotypic data of 40 individuals with previously nondiagnostic clinical exomes were reanalyzed with current software and literature. A definitive diagnosis was identified for 4 of 40 participants (10%). In these cases the causative variant is de novo and in a relevant autosomal-dominant disease gene. The literature to tie the causative genes to the participants' phenotypes was weak, nonexistent, or not readily located at the time of the initial clinical exome reports. At the time of diagnosis by reanalysis, the supporting literature was 1 to 3 years old. Approximately 250 gene-disease and 9,200 variant-disease associations are reported annually. This increase in information necessitates regular reevaluation of nondiagnostic exomes. To be practical, systematic reanalysis requires further automation and more up-to-date variant databases. To maximize the diagnostic yield of exome sequencing, providers should periodically request reanalysis of nondiagnostic exomes. Accordingly, policies regarding reanalysis should be weighed in combination with factors such as cost and turnaround time when selecting a clinical exome laboratory.Genet Med 19 2, 209-214.

Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield

Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.

Exome Sequencing as a Diagnostic Tool for Pediatric‐Onset Ataxia

Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease genes for rare pediatric diseases using whole-exome sequencing. We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families, we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative.