Abstract
Lysosomal diseases (LD) are a group of about 70 rare hereditary disorders (combined incidence 1:5000) in which diverse lysosomal functions are impaired, impacting multiple organs and systems. The first clinical signs and symptoms are usually unspecific and shared by hundreds of other disorders. Diagnosis of LD traditionally relies on performing specific enzymatic assays, if available, upon clinical suspicion of the disorder. However, the combination of the insidious onset of LD and the lack of awareness on these rare diseases among medical personnel results in undesirable diagnostic delays, with unchecked disease progression, appearance of complications and a worsened prognosis. We tested the usefulness of a next‐generation sequencing‐based gene panel for quick, early detection of LD among cases of idiopathic splenomegaly and/or thrombocytopenia, two of the earliest clinical signs observed in most LD. Our 73‐gene panel interrogated 28 genes for LD, 1 biomarker and 44 genes underlying non‐LD differential diagnoses. Among 38 unrelated patients, we elucidated eight cases (21%), five with LD (GM1 gangliosidosis, Sanfilippo disease A and B, Niemann‐Pick disease B, Gaucher disease) and three with non‐LD conditions. Interestingly, we identified three LD patients harboring pathogenic mutations in two LD genes each, which may result in unusual disease presentations and impact treatment. Turnaround time for panel screening and genetic validation was 1 month. Our results underline the usefulness of resequencing gene panels for quick and cost‐effective screening of LDs and disorders sharing with them early clinical signs.
Highlights
Lysosomal diseases (LD) are a group of about 70 rare hereditary disorders in which lysosomal function is altered due to pathogenic mutations that affect the genes encoding lysosomal proteins such as hydrolases, transporters, receptors, enzyme activators and so on
Since splenomegaly and/or thrombocytopenia are recognizable signs that are among the earliest clinical signs in many LD, we reasoned that screening of cases with idiopathic splenomegaly and/or thrombocytopenia with a gene panel designed to target genes whose mutations underlie such those two signs might lead to early detection of some LD cases
In this work we have tested the usefulness of next-generation sequencing (NGS), genepanel-based genetic screening for disorders underlying two very common clinical signs in the hematology consultation, splenomegaly and thrombocytopenia, for early detection of LD
Summary
Lysosomal diseases (LD) are a group of about 70 rare hereditary disorders in which lysosomal function is altered due to pathogenic mutations that affect the genes encoding lysosomal proteins such as hydrolases, transporters, receptors, enzyme activators and so on. Two factors contribute to this delay: (a) the insidious onset of many LD, with early symptoms and signs that are unspecific, easy to overlook and common to many other conditions; (b) the rarity of LD, which causes a lack of awareness on these disorders among nonspecialist physicians.[2]. This diagnostic delay is highly undesirable because it may result in unchecked progression of the disorder, application of inappropriate treatments, the onset of complications (including anxiety and stress), a worsened prognosis and the lack of familial counselling. We report on the design, validation and testing of an NGS-based resequencing panel for genes underlying disorders with splenomegaly or thrombocytopenia among their clinical signs, with specific focus on LD
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