Next-generation sequencing (NGS) may be a useful tool for the detection and diagnosis of lysosomal storage diseases (LSDs) including lysosomal acid lipase deficiency (LAL-D) and Pompe disease.

According to a review article published in Biomedicines, as NGS technologies advance and become more available, they offer faster, cheaper, and higher-resolution testing options to identify point mutations, small gene insertions and deletions (indels), and significant structural variants (SVs) responsible for LSDs.

“Conventional diagnostic procedures are able to identify and diagnose most individuals with LSDs. However, a number of cases remain unexplained for difficulties in detecting [copy number variants (CNVs)] or other complex rearrangements altering gene expression and enzymatic function,” the study’s authors said.

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“Numerous case-reports have highlighted the advantages obtained by the use of NGS for the diagnostic validation of LSDs, especially for the detection of SVs in cases for which conventional procedures determine insufficient evidence,” they added.

Read more about LAL-D testing

A number of mutations related to lipid storage diseases have been described in the literature, including a specific case of LAL-D where NGS was utilized. In the case, a 4-month-old infant who presented with failure to thrive, hepatosplenomegaly, and other abnormalities was found to carry a homozygous deletion of exons 9-10 of the LIPA gene, leading to a diagnosis of LAL-D, specifically Wolman disease.

Several CNVs have also been described for patients with Pompe disease including deletion of exon 18 (the most common), deletion of exons 2-3, exons 2-4, introns 7-15, introns 17-18, and exons 15-20.

While NGS can be a useful tool for the detection of genetic changes, the authors highlight some challenges with its use. Currently, no single informatic method exists to identify structural DNA variations, and the SV detection algorithms available range in their false-positive and false-negative rates.

The clinical relevance of SVs, especially CNVs, remains a challenge, as their pathogenicity is not always known— especially for nonrecurrent or de novo SVs. The authors highlighted the need for analysis to be performed on the effect the mutation has on downstream metabolic activity, along with the protein and mRNAs generated, before SVs are reported in a diagnostic report.


La Cognata V, Cavallaro S. Detection of structural variants by NGS: Revealing missing alleles in lysosomal storage diseases. Biomedicines. 2022;10(8):1836. doi:10.3390/biomedicines10081836