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The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics.

ABSTRACT: Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.

SUBMITTER: Dratch L

PROVIDER: S-EPMC10886886 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics.

Dratch Laynie L Bardakjian Tanya M TM Johnson Kelsey K Babaian Nareen N Gonzalez-Alegre Pedro P Elman Lauren L Quinn Colin C Guo Michael H MH Scherer Steven S SS Amado Defne A DA

Biology 20240202 2

Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to ...[more]

PMID: 38392311

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Project description:ImportanceEpilepsy is the most common neurological disorder of childhood. Identifying genetic diagnoses underlying epilepsy is critical to developing effective therapies and improving outcomes. Most children with non-acquired (unexplained) epilepsy remain genetically unsolved, and the utility of genome sequencing after nondiagnostic exome sequencing is unknown.ObjectiveTo determine the diagnostic (primary) and clinical (secondary) utility of genome sequencing after nondiagnostic exome sequencing in individuals with unexplained pediatric epilepsy.DesignThis cohort study performed genome sequencing and comprehensive analyses for 125 participants and available biological parents enrolled from August 2018 to May 2023, with data analysis through April 2024 and clinical return of diagnostic and likely diagnostic genetic findings. Clinical utility was evaluated.SettingPediatric referral center.ParticipantsParticipants with unexplained pediatric epilepsy and previous nondiagnostic exome sequencing; biological parents when available.ExposuresShort-read genome sequencing and analysis.Main outcomes and measuresPrimary outcome measures were the diagnostic yield of genome sequencing, defined as the percentage of participants receiving a diagnostic or likely diagnostic genetic finding, and the unique diagnostic yield of genome sequencing, defined as the percentage of participants receiving a diagnostic or likely diagnostic genetic finding that required genome sequencing. The secondary outcome measure was clinical utility of genome sequencing, defined as impact on evaluation, treatment, or prognosis for the participant or their family.Results125 participants (58 [46%] female) were enrolled with median age at seizure onset 3 [IQR 1.25, 8] years, including 44 (35%) with developmental and epileptic encephalopathies. The diagnostic yield of genome sequencing was 7.2% (9/125), with diagnostic genetic findings in five cases and likely diagnostic genetic findings in four cases. Among the solved cases, 7/9 (78%) required genome sequencing for variant detection (small copy number variant, three noncoding variants, and three difficult to sequence small coding variants), for a unique diagnostic yield of genome sequencing of 5.6% (7/125). Clinical utility was documented for 4/9 solved cases (44%).Conclusions and relevanceThese findings suggest that genome sequencing can have diagnostic and clinical utility after nondiagnostic exome sequencing and should be considered for patients with unexplained pediatric epilepsy.

Dataset Information

The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics.

Publications

The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics.

Similar Datasets

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