Dataset Information

Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico.

ABSTRACT: Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (n?=?41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (n?=?20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (n?=?20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.

SUBMITTER: Scocchia A

PROVIDER: S-EPMC6375919 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico.

Scocchia Alicia A Wigby Kristen M KM Masser-Frye Diane D Del Campo Miguel M Galarreta Carolina I CI Thorpe Erin E McEachern Julia J Robinson Keisha K Gross Andrew A Ajay Subramanian S SS Rajan Vani V Perry Denise L DL Belmont John W JW Bentley David R DR Jones Marilyn C MC Taft Ryan J RJ

NPJ genomic medicine 20190214

Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil ...[more]

PMID: 30792901

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Project description:BackgroundScreening for short tandem repeat (STR) expansions in next-generation sequencing data can enable diagnosis, optimal clinical management/treatment, and accurate genetic counseling of patients with repeat expansion disorders. We aimed to develop an efficient computational workflow for reliable detection of STR expansions in next-generation sequencing data and demonstrate its clinical utility.MethodsWe characterized the performance of eight STR analysis methods (lobSTR, HipSTR, RepeatSeq, ExpansionHunter, TREDPARSE, GangSTR, STRetch, and exSTRa) on next-generation sequencing datasets of samples with known disease-causing full-mutation STR expansions and genomes simulated to harbor repeat expansions at selected loci and optimized their sensitivity. We then used a machine learning decision tree classifier to identify an optimal combination of methods for full-mutation detection. In Burrows-Wheeler Aligner (BWA)-aligned genomes, the ensemble approach of using ExpansionHunter, STRetch, and exSTRa performed the best (precision = 82%, recall = 100%, F1-score = 90%). We applied this pipeline to screen 301 families of children with suspected genetic disorders.ResultsWe identified 10 individuals with full-mutations in the AR, ATXN1, ATXN8, DMPK, FXN, or HTT disease STR locus in the analyzed families. Additional candidates identified in our analysis include two probands with borderline ATXN2 expansions between the established repeat size range for reduced-penetrance and full-penetrance full-mutation and seven individuals with FMR1 CGG repeats in the intermediate/premutation repeat size range. In 67 probands with a prior negative clinical PCR test for the FMR1, FXN, or DMPK disease STR locus, or the spinocerebellar ataxia disease STR panel, our pipeline did not falsely identify aberrant expansion. We performed clinical PCR tests on seven (out of 10) full-mutation samples identified by our pipeline and confirmed the expansion status in all, showing absolute concordance between our bioinformatics and molecular findings.ConclusionsWe have successfully demonstrated the application of a well-optimized bioinformatics pipeline that promotes the utility of genome-wide sequencing as a first-tier screening test to detect expansions of known disease STRs. Interrogating clinical next-generation sequencing data for pathogenic STR expansions using our ensemble pipeline can improve diagnostic yield and enhance clinical outcomes for patients with repeat expansion disorders.

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Dataset Information

Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico.

Publications

Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico.

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