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Diagnostic value of repeat expansion disorders detected in genome sequencing data

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Genomic Medicine
  • Secondary Categories:
    • Genomic Medicine
Introduction:
Repeat expansions are a known cause of over 40 genetic disorders, and there are likely more yet to be discovered. Detection of repeat expansions typically requires specialized and phenotype-directed testing, and precludes evaluation of novel repeat expansion disorders. Genome sequencing offers a broader diagnostic approach for individuals with suspected genetic disorders, however there are technical challenges with detecting repeat expansions in short-read genome sequencing (SR-GS) data. Recently, methods are being developed to enable detection of known and novel repeat expansions using SR-GS data.

Methods:
To investigate repeat expansion disorders in individuals with rare disease, members of the University of Miami Undiagnosed Diseases Network (UDN) site ran the ExpansionHunter Denovo (EHDn) pipeline on SR-GS data from individuals enrolled in the UDN study. Notable findings were shared with individual UDN clinical sites for review of findings in the context of their individual case(s). For UDN participants enrolled at the Stanford Center for Undiagnosed Diseases, clinical validation was performed when indicated and available. Additionally, long read genome sequencing and RNA sequencing were performed at Stanford for a subset of cases to better characterize repeat expansion sizes and potential effects on gene expression.

Results:
EHDn identified diagnostic and likely diagnostic repeat expansions in 7 individuals from 6 unrelated families. Diagnostic findings in established disease-associated genes included biallelic repeat expansions in RFC1 in 2 unrelated individuals, a heterozygous repeat expansion in TBP that had been missed by prior targeted clinical testing, and heterozygous repeat expansions in CNBP and HTT. Expansions were clinically validated in 4 of these individuals and 1 is currently pending. Additionally, a novel heterozygous CGG repeat expansion in the 5’UTR of FAM193B was detected in 2 affected siblings with oculopharyngeal myopathy (OPDM). These sisters first developed symptoms at ages 49 and 51 years, which include progressive muscle weakness in extremities and face, voice changes, and ptosis. Additional features in the proband include diplopia, dysarthria, dysphagia, and skeletal muscle biopsy showing chronic myopathy and rimmed vacuoles. Orthogonal validation using long read sequencing predicted repeat sizes of ~245 and ~220 in the affected sisters and ~180 in their unaffected mother. RNA sequencing from blood showed that both sisters are overexpression outliers for the FAM193B gene compared to 282 UDN participants. FAM193B does not currently have an established gene-disease association, however CGG repeat expansions in the 5’UTR of two other genes are known causes of OPDM. This FAM193B expansion is considered a candidate diagnosis for the family and further work to establish this novel gene-disease association is ongoing.

Conclusion:
Detection of known and novel repeat expansions in SR-GS data offers a promising avenue for a broader approach to diagnosis of both known and novel repeat expansion disorders in individuals with rare and undiagnosed disease. With continued development and more widespread application, this can facilitate earlier diagnosis for individuals on a diagnostic odyssey.

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