The Role of Next-Generation Sequencing in the Diagnosis of Lysosomal Storage Disorders

Abstract

Next-generation sequencing (NGS) panels are used widely in clinical diagnostics to identify genetic causes of various monogenic disease groups including neurometabolic disorders and, more recently, lysosomal storage disorders (LSDs). Many new challenges have been introduced through these new technologies, both at the laboratory level and at the bioinformatics level, with consequences including new requirements for interpretation of results, and for genetic counseling. We review some recent examples of the application of NGS technologies, with purely diagnostic and with both diagnostic and research aims, for establishing a rapid genetic diagnosis in LSDs. Given that NGS can be applied in a way that takes into account the many issues raised by international consensus guidelines, it can have a significant role even early in the course of the diagnostic process, in combination with biochemical and clinical data. Besides decreasing the delay in diagnosis for many patients, a precise molecular diagnosis is extremely important as new therapies are becoming available within the LSD spectrum for patients who share specific types of mutations. A genetic diagnosis is also the prerequisite for genetic counseling, family planning, and the individual choice of reproductive options in affected families.

Identifying the genetic causes of phenotypically diagnosed Pakistani mucopolysaccharidoses patients by whole genome sequencing

“…For this reason, the incorporation of next-generation sequencing (NGS) in consanguineous families represents one of the best ways to elucidate the underlying causes in rare diseases such as MPS I and MPS II and establish a genotype-phenotype relationship ( Hoffman et al, 2013 ; Umair et al, 2018 ). NGS will not only be helpful in the correct diagnosis of the disease but it will also help in prenatal testing, family planning, carrier testing and genetic counseling in families affected with LSDs ( Komlosi et al, 2016 ). Similarly, dual molecular diagnosis has been reported in several cases of consanguineous unions ( Umair et al, 2017 ), which cannot be detected through conventional sequencing or enzymatic testing.…”

Cardiac Murmur in a Boy with Normal Paternal Prenatal Carrier Screening for Pompe Disease

“…Patients should be counseled about the limitations of genetic technology, and understandably with the amount of conditions tested for they may not recall whether they were positive or negative for a specific condition. Pediatricians should also be aware of the limitations of current genetic technology; while in the past Sanger sequencing was used today, many current panels use next generation sequencing (NGS) for patient testing [4]. is method allows for the generation of massive amounts of data from an individual patient through sequencing millions of fragments in a parallel manner.…”

Highlights on Genomics Applications for Lysosomal Storage Diseases

“…Further concerns regard the professional responsibility and individual or In a practical diagnostic setting, the goal of genome-scale sequencing is to identify genetic variants so as to provide a molecular etiology for patients' clinical manifestations, considering all other variants as incidental findings. The high-throughput ability of NGS has been successfully used to diagnose LSDs [54][55][56][57][58][59], both in the form of exome and targeted sequencing. This is particularly useful when applied to specific diagnostic contexts, including carrier screening studies in high-risk populations (e.g., the Ashkenazi Jewish population) [60,61], prenatal diagnosis [62], unsolved cases where traditional molecular diagnostic approaches have failed [63], unclear or suspected LSD cases [64,65], as well as in defining genotype-phenotype correlations [66] or to find out genetic disease modifiers [67].…”