NGS-Based Genetic Approach to Identify Rare Lysosomal Storage Disorders in Patients With Neurological Manifestations

Condition(s) studied

Investigational drug(s) / intervention(s)

NGS-based genetic testing: A single peripheral venous blood collection (two 7 mL EDTA tubes) is used for DNA extraction and whole-exome sequencing in all participants. First-line analysis uses the Nextera Exome Library protocol and Illumina NextSeq500 platform, followed by bioinformatic analysis for causal variants. Approximately 10 selected participants with unresolved findings and strong suspicion of a lysosomal storage disorder undergo second-line long-read sequencing without an additional blood collection. Testing is preceded by genetic counseling and followed by clinical reassessment and, for participants who choose to receive results, a genetic report and post-test counseling. The genetic analysis phase is expected to last approximately six months.

Study summary

LYSO-NEXT uses genetic sequencing to identify undiagnosed lysosomal storage disorders in adults with unexplained neurological symptoms. Participants undergo whole-exome sequencing, which examines the protein-coding regions of DNA. A small subgroup with inconclusive results and strong clinical suspicion undergoes additional long-read sequencing to detect genetic changes that may be missed by the initial test. The study assesses the proportion of participants diagnosed with a lysosomal storage disorder and the diagnostic yield of each sequencing approach.

Eligibility

Primary outcome measure(s)

• Prevalence of genetically diagnosed lysosomal storage disorders — At completion of genetic analysis and clinical reassessment, approximately 6 months after blood sampling
  Proportion of enrolled participants with a genetically diagnosed lysosomal storage disorder, calculated as the number of participants diagnosed with a lysosomal storage disorder divided by the total number of participants recruited. Genetic findings are assessed together with clinical reassessment to establish genotype-phenotype compatibility.

Trial sites (1)

More Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico trials in Italy

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