Clinical utility of multigene analysis in over 25,000 patients with neuromuscular disorders

Winder, Thomas; Tan, Christopher; Klemm, Sarah; White, Hannah; Westbrook, Jody; Wang, James; Entezam, Ali; Truty, Rebecca; Nussbaum, Robert L.; McNally, Elizabeth M.; Aradhya, Swaroop

doi:10.1212/nxg.0000000000000412

Cited by 39 publications

(49 citation statements)

References 28 publications

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“…Their panel is sequenced to high depth (50x minimum) to detect SNVs, indels, exon-level deletions/duplications, and large copy number variants. Among 1,910 patients with a clinical diagnosis of dystonia included in a recent report, 7.9% were given a molecular diagnosis and 11.8% were found to have a variant of unknown significance [ 27 ]. The genes with highest yield were SGCE (20.5%) and TOR1A (19.9%) [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Among 1,910 patients with a clinical diagnosis of dystonia included in a recent report, 7.9% were given a molecular diagnosis and 11.8% were found to have a variant of unknown significance [ 27 ]. The genes with highest yield were SGCE (20.5%) and TOR1A (19.9%) [ 27 ]. For comparison, within the ClinVar database on July 3, 2020, there are 215 accessions associated with SGCE , but only 122 associated with TOR1A .…”

Section: Discussionmentioning

confidence: 99%

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Population Prevalence of Deleterious <i>SGCE</i> Variants

LeDoux

2020

Tremor and Other Hyperkinetic Movements

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Background: Myoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in SGCE , a maternally imprinted gene, are the most frequent known genetic cause of M-D. The population prevalence of SGCE -linked M-D is unknown, the pathogenicity of SGCE variants identified in patients with M-D may be indeterminant, and SGCE variants predicted to be deleterious by in silico analysis may appear in patients undergoing whole-exome or whole-genome sequencing for seemingly unrelated disorders. The Genome Aggregation Database (gnomAD) v2 provides variant data on 125,748 exomes and 15,708 genomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies. Methods: SGCE variants included in the gnomAD v2 dataset were analyzed with Combined Annotation Dependent Depletion (CADD), and database for nonsynonymous single nucleotide polymorphisms’ functional predictions (dbNSFP). We determined the frequency of annotated SGCE variants, ranked by scores of deleteriousness, within the gnomAD v2 dataset. Deleteriousness scores were compared to a subset of published disease associated SGCE pathogenic variants. Results: Within gnomAD v2, there were 56, 408, and 1250 alleles harboring SGCE variants with CADD scores greater than 30, 25, and 20, respectively. We estimate that approximately 1/348 individuals in the United States population harbors an SGCE variant with a CADD score ≥ 25. Discussion: SGCE M-D may be underdiagnosed due to pleiotropy, mild phenotypes, variable penetrance, and impaired access to genetic testing. Due to the high population prevalence of deleterious SGCE variants, caution should be used when asserting pathogenicity without co-segregation analyses and expert neurological examination of phenotypes within pedigrees. Highlights In silico analyses of a large population database of genetic variants revealed that over 0.2% of individuals in the United States harbor a highly deleterious SGCE variant. This finding suggests that M-D and minor phenotypic variants such as mild isolated myoclonus may be underdiagnosed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Population Prevalence of Deleterious <i>SGCE</i> Variants

LeDoux

2020

Tremor and Other Hyperkinetic Movements

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“…All individual samples were extracted, sequenced, and analyzed in Invitae's accredited and certified molecular diagnostic laboratory as described previously ( 11 , 12 ). The NGS-based Spinal Muscular Atrophy Panel sequenced SMN1 and SMN2 at high-depth coverage (50 × minimum, 350 × average).…”

Section: Methodsmentioning

confidence: 99%

“…The coding regions of SMN1 and SMN2 differ by a single nucleotide variant at position c.840 in exon 7, commonly referred to as the gene-determining variant, which is used to determine SMN1 and SMN2 copy number. A next-generation sequencing (NGS)-based method has been developed that enables simultaneous sequencing and copy number analysis of SMN1 and SMN2 and addresses inherent limitations of traditional SMA testing methods (9)(10)(11)(12). However, long-range (LR)-PCR is still required to distinguish single nucleotide variants in SMN1 from those in SMN2.…”

Section: Introductionmentioning

confidence: 99%

SMA Identified: Clinical and Molecular Findings From a Sponsored Testing Program for Spinal Muscular Atrophy in More Than 2,000 Individuals

et al. 2021

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Background: Spinal muscular atrophy (SMA) linked to chromosome 5q is an inherited progressive neuromuscular disorder with a narrow therapeutic window for optimal treatment. Although genetic testing provides a definitive molecular diagnosis that can facilitate access to effective treatments, limited awareness and other barriers may prohibit widespread testing. In this study, the clinical and molecular findings of SMA Identified—a no-charge sponsored next-generation sequencing (NGS)-based genetic testing program for SMA diagnosis—are reported.Methods: Between March 2018 and March 2020, unrelated individuals who had a confirmed or suspected SMA diagnosis or had a family history of SMA were eligible. All individuals underwent diagnostic genetic testing for SMA at clinician discretion. In total, 2,459 individuals were tested and included in this analysis. An NGS-based approach interrogated sequence and copy number of SMN1 and SMN2. Variants were confirmed by multiplex ligation-dependent probe amplification sequencing. Individuals were categorized according to genetic test results: diagnostic (two pathogenic SMN1 variants), nearly diagnostic (SMN1 exon-7 deletion with a variant of uncertain significance [VUS] in SMN1 or SMN2), indeterminate VUS (one VUS in SMN1 or SMN2), carrier (heterozygous SMN1 deletion only), or negative (no pathogenic variants or VUS in SMN1 or SMN2). Diagnostic yield was calculated. Genetic test results were analyzed based on clinician-reported clinical features and genetic modifiers (SMN2 copy number and SMN2 c.859G>C).Results: In total, 2,459 unrelated individuals (mean age 24.3 ± 23.0 years) underwent diagnostic testing. The diagnostic yield for diagnostic plus nearly diagnostic results was 31.3% (n = 771/2,459). Age of onset and clinical presentation varied considerably for individuals and was dependent on SMN2 copy number. Homozygous deletions represented the most common genetic etiology (96.2%), with sequence variants also observed in probands with clinical diagnoses of SMA.Conclusions: Using a high-yield panel test in a no-charge sponsored program early in the diagnostic odyssey may open the door for medical interventions in a substantial number of individuals with SMA. These findings have potential implications for clinical management of probands and their families.

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“…Genomic coordinates were identified for all target regions in the 122 genes, and all exons and exon-intron junctions were sequenced at high-depth coverage (50 • minimum, 350 • average) to simultaneously identify single nucleotide variants, short and long insertions and deletions, exon-level deletion/duplications or copy number variants, and rare structural rearrangements that disrupt coding sequence. NGS panel testing and clinical variant interpretation were performed as described previously (Nykamp et al, 2017;Winder et al, 2020). As per IRB approval (Western IRB No.…”

Section: Neuromuscular Disorders Panelmentioning

confidence: 99%

Incorporating Spinal Muscular Atrophy Analysis by Next-Generation Sequencing into a Comprehensive Multigene Panel for Neuromuscular Disorders

Tan

Westbrook

Truty

et al. 2020

Genetic Testing and Molecular Biomarkers

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Background: Spinal muscular atrophy (SMA) is traditionally molecularly diagnosed by multiplex ligationdependent probe amplification or quantitative polymerase chain reaction (qPCR). SMA analyses are not routinely incorporated into gene panel analyses for individuals with suspected SMA or broader neuromuscular indications. Aim: We sought to determine whether a next-generation sequencing (NGS) approach that integrates SMA analyses into a multigene neuromuscular disorders panel could detect undiagnosed SMA. Materials and Methods: Sequence and copy number variants of the SMN1/SMN2 genes were simultaneously analyzed in samples from 5304 unselected individuals referred for testing using an NGS-based 122-gene neuromuscular panel. This diagnostic approach was validated using DNA from 68 individuals who had been previously diagnosed with SMA via quantitative PCR for SMN1/SMN2. Results: Homozygous loss of SMN1 was detected in 47 unselected individuals. Heterozygous loss of SMN1 was detected in 118 individuals; 8 had an indeterminate variant in ''SMN1 or SMN2'' that supported an SMA diagnosis but required additional disambiguation. Of the remaining SMA carriers, 44 had pathogenic variants in other genes. Concordance rates between NGS and qPCR were 100% and 93% for SMN1 and SMN2 copy numbers, respectively. Where there was disagreement, phenotypes were more consistent with the SMN2 results from NGS. Conclusion: Integrating NGS-based SMA testing into a multigene neuromuscular panel allows a single assay to diagnose SMA while comprehensively assessing the spectrum of variants that can occur in individuals with broad differential diagnoses or nonspecific/overlapping neuromuscular features.

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Clinical utility of multigene analysis in over 25,000 patients with neuromuscular disorders

Cited by 39 publications

References 28 publications

Population Prevalence of Deleterious <i>SGCE</i> Variants

Population Prevalence of Deleterious <i>SGCE</i> Variants

SMA Identified: Clinical and Molecular Findings From a Sponsored Testing Program for Spinal Muscular Atrophy in More Than 2,000 Individuals

Incorporating Spinal Muscular Atrophy Analysis by Next-Generation Sequencing into a Comprehensive Multigene Panel for Neuromuscular Disorders

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