Prof. Huseyin Onay

Genetics of Lysosomal Storage Disorders

Lysosomal storage diseases (LSDs) are heritable errors of metabolism that affect the function of the lysosome. LSDs comprise a group of 70 monogenic disorders of lysosomal catabolism, most of which are inherited as autosomal recessive traits, but three are X- linked. These disorders are caused by mutations in genes encoding lysosomal proteins, such as lysosomal glycosidases, proteases, integral membrane proteins, transporters, enzyme modifiers or activators. Some forms of the LSDs such as Pompe, Fabry, Mucopolysaccharidosis Type 1 and Gaucher are treatable. These lifesaving and life changing therapies prevent life-threatening symptoms of the diseases. These four different LSDs have different clinical presentations and different clinical and genetic diagnostic algorithms. Diagnostic delay in LSDs is a common problem. Rapid genetic diagnosis of these 4 treatable diseases prevents patients to develop disease related symptoms.

Prof. Ahmed Alfares

Variant analysis and interpretation of lysosomal storage diseases

Whole exome sequencing data interpretation is difficult, requiring a lot of time and effort to go over all of the variants in the variant call format. However, in storage diseases, a custom filtration approach can be used to hunt primarily for homozygous variants in autosomal recessive illnesses. In storage disorders, the majority of disease-causing mutations were homozygous and the number of candidate variants requiring further analysis decreases dramatically when using a proprietary filtration procedure, while retaining a high detection rate and completing analysis in less time. For example, Pompe disease is caused by a lack of acid alpha-glucosidase, which is encoded by GAA (glycogen storage disease type II; acid maltase deficiency), accurate interpretation of variants within GAA is critical. DNA variants in GAA is used as an example in this talk as an approved LSD gene in ClinGen by the Lysosomal Storage Disorders Variant Curation Expert Panel, Clinical Domain Working Groups.