Lysosomal Storage Disorders Panel

Lysosomal storage disorders are rare inborn errors of metabolism characterized by lysosomal dysfunction, often presenting with neurodegeneration, visceromegaly, metabolic dysfunction, and impaired growth in infancy and childhood, with symptom onset as early as the prenatal period and as late as adulthood (Platt et al. 2018. PubMed ID: 30275469). Lysosomes are membrane-bound organelles that serve as the primary degradative compartment of eukaryotic cells, and play an important role in removal of toxic cellular components, elimination of ‘worn-out’ organelles, termination of signal transduction, and maintenance of metabolic homeostasis (Ballabio and Bonifacino. 2020. PubMed ID: 31768005). At the molecular level, lysosomal storage disorders result from a biochemical deficiency of key lysosomal proteins such as hydrolases, which breakdown complex macromolecules into amino acids, monosaccharides, and free fatty acids, and permeases, which facilitate transport of macromolecules across the limiting membrane of the lysosome, as well as non-lysosomal proteins that are important for lysosomal function (Platt et al. 2018. PubMed ID: 30275469). Defects that impair breakdown or transport of complex macromolecules and their products lead to the accumulation (or storage) of undigested or partially digested macromolecules in the lysosomes, which ultimately results in cellular damage and disease (Seranova et al. 2017. PubMed ID: 29233882; Marques and Saftig. 2019. PubMed ID: 30651381). While neurodegeneration is a major clinical feature of many lysosomal storage disorders, clinical manifestations often involve multiple organ systems and can be systemic in nature. Other clinical features of lysosomal storage disorders may include dysmorphic facial features, hearing and vision impairment, bone and joint involvement, skin abnormalities, as well as pulmonary, gastrointestinal, cardiovascular, and hematological symptoms (Platt et al. 2018. PubMed ID: 30275469).

Lysosomal storage disorders are individually rare, but collectively common, with a worldwide incidence estimated at 1:5,000 (Platt et al. 2018. PubMed ID: 30275469). Incidences for individual disorders vary by population, with some lysosomal storage disorders occurring more frequently in certain ethnic groups and geographic regions due to founder effects (Nalysnyk et al. 2017. PubMed ID: 27762169; Leslie et al. 2017. PubMed ID: 20301438), and in ethnic groups where consanguineous marriage is prevalent (Elmonem et al. 2016. PubMed ID: 26830282).

A molecular diagnosis may aid in implementation of a therapeutic strategy for patients with a lysosomal storage disorder. Presymptomatic and early treatment with disease specific interventions, including enzyme replacement, substrate reduction, and chaperone therapies, can slow the progression of some lysosomal storage disorders (Platt. 2018. PubMed ID: 29147032). Patients and their families may also benefit from a molecular diagnosis for prognostic information, symptom management, and reproductive planning.

This test includes ~70 genes known to be monogenic causes of lysosomal storage disorders (Platt et al. 2018. PubMed ID: 30275469), as well as genes for disorders that may be difficult to distinguish phenotypically from lysosomal storage disorders. Genes were identified through the literature, OMIM, and HGMD searches.

Lysosomal storage disorders are clinically and genetically heterogeneous. The vast majority of lysosomal storage disorders are inherited in an autosomal recessive (AR) manner, but may also be inherited in an X-linked (XL) manner (such as Mucopolysaccharidosis II, Danon disease, and Fabry disease) or an autosomal dominant (AD) manner (such as neuronal ceroid lipofuscinosis-4B).

Disorders resulting from defects in sphingolipid metabolism, commonly referred to as the sphingolipidoses, are among the most prevalent subtypes of lysosomal storage disorders, with a combined incidence of approximately 1:10,000 (Genetics Home Reference; Kolter and Sandhoff. 2006. PubMed ID: 16854371). For example, biallelic pathogenic variants in GBA1/GBA result in autosomal recessive Gaucher disease, a sphingolipidosis characterized by acidic glucocerebrosidase enzyme deficiency and therefore aberrant accumulation of the sphingolipid glucosylceramide within the lysosome (Pastores et al. 2018. PubMed ID: 20301446). Pathogenic variants in GLA result in X-linked Fabry disease, an inborn error of glycosphingolipid catabolism caused by alpha-galactosidase A enzyme deficiency and therefore aberrant accumulation of globotriaoslyceramide (Gb3) within the lysosome (Mehta et al. 2017. PubMed ID: 20301469). Gaucher disease is estimated to account for ~13% of all lysosomal storage disorder cases, while Fabry disease is estimated to account for ~7% of all lysosomal storage disorder cases (Meikle et al. 1999. PubMed ID: 9918480; Poorthuis et al. 1999. PubMed ID: 10480370; Pinto et al. 2004. PubMed ID: 14685153; Poupetová et al. 2010. PubMed ID: 20490927; Kadali et al. 2014. PubMed ID: 24700663; Elmonem et al. 2016. PubMed ID: 26830282).

Disorders resulting from defects in glycosaminoglycan catabolism, commonly referred to as the mucopolysaccharidoses, are a similarly prevalent subtype of lysosomal storage disorders, with a combined incidence of approximately 1:20,000 to 1:25,000 (Genetics Home Reference; Cimaz and La Torre. 2014. PubMed ID: 24264718; Kondo et al. 2017. PubMed ID: 28013294). For example, biallelic pathogenic variants in IDUA result in autosomal recessive mucopolysaccharidosis type I (MPSI) as a result of alpha-L-iduronidase deficiency and aberrant accumulation of the glycosaminoglycans dermatan sulfate and heparin sulfate (Clarke and Clarke. 2016. PubMed ID: 20301341). Pathogenic variants IDS cause X-linked recessive mucopolysaccharidosis type II (MPSII), characterized by iduronate sulfatase deficiency and aberrant accumulation of the same glycosaminoglycans dermatan sulfate and heparin sulfate (Scarpa and Scarpa. 2018. PubMed ID: 20301451). Notably, MPSI and MPSII account for approximately ~14% of all lysosomal storage disorder cases (Meikle et al. 1999. PubMed ID: 9918480; Poorthuis et al. 1999. PubMed ID: 10480370; Pinto et al. 2004. PubMed ID: 14685153; Poupetová et al. 2010. PubMed ID: 20490927; Kadali et al. 2014. PubMed ID: 24700663; Elmonem et al. 2016. PubMed ID: 26830282).

Biallelic pathogenic variants in GAA cause autosomal recessive Pompe disease as a result of acid alpha glucosidase deficiency and progressive accumulation of glycogen in lysosomes (Leslie et al. 2017. PubMed ID: 20301438). Pompe disease is similarly prevalent with an estimated incidence of 1:40,000 people in the United States (Genetics Home Reference), with increased incidence of up to 1:14,000 among African Americans (Leslie et al. 2017. PubMed ID: 20301438). Pompe disease accounts for ~9% of all diagnosed lysosomal storage disorder cases (Meikle et al. 1999. PubMed ID: 9918480; Poorthuis et al. 1999. PubMed ID: 10480370; Pinto et al. 2004. PubMed ID: 14685153; Poupetová et al. 2010. PubMed ID: 20490927; Kadali et al. 2014. PubMed ID: 24700663; Elmonem et al. 2016. PubMed ID: 26830282).

Combined, these five (Gaucher and Fabry disease, Muccopolysaccharidosis types I and II, and Pompe disease) of the ~70 monogenic lysosomal storage disorders are estimated to account for approximately 40% of all diagnosed cases (Meikle et al. 1999. PubMed ID: 9918480; Poorthuis et al. 1999. PubMed ID: 10480370; Pinto et al. 2004. PubMed ID: 14685153; Poupetová et al. 2010. PubMed ID: 20490927; Kadali et al. 2014. PubMed ID: 24700663; Elmonem et al. 2016. PubMed ID: 26830282).  A wide variety of causative variants in the ~70 monogenic lysosomal storage disorders genes have been reported including missense, nonsense, splicing, small insertions/deletions, large deletions/duplications and complex rearrangements (Human Gene Mutation Database). Pseudodeficiency alleles, or clinically benign gene variants that result in reduced biochemical activity, have also been associated with Tay-Sachs disease (HEXA), Pompe disease (GAA), metachromatic leukodystrophy (ARSA), MPS I (IDUA), GM1-gangliosidosis (GLB1), Krabbe disease (GALC), Sandhoff disease (HEXB), Fabry disease (GLA), MPS VII (GUSB), and fucosidosis (FUCA).

See individual gene summaries for information about the molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the disorders tested in this panel, the clinical sensitivity of this specific grouping of genes is difficult to estimate. In retrospective studies, approximately 20-30% of patients with a clinical suspicion of a lysosomal storage disease were enzymatically diagnosed (Kadali et al. 2014. PubMed ID: 24700663; Elmonem et al. 2016. PubMed ID: 26830282). This panel includes all known monogenic causes of lysosomal storage disorders (Platt et al. 2018. PubMed ID: 30275469), thus maximum possible clinical sensitivity should be obtained.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.5% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).