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

Front Genet. 2023 Apr 5;14:1128850. doi: 10.3389/fgene.2023.1128850.

PMID: 37091798

Rutaba Gul, Sabika Firasat, Mikkel Schubert

Highlights: The aim of the present study was to identify novel genes and pathogenic variants in families from diverse regions of Pakistan with clinically diagnosed mucopolysaccharidosis type I and mucopolysaccharidosis type II.

Abstract

Background: Over 50 different kinds of pathologies make up the group of hereditary metabolic diseases known as lysosomal storage disorders (LSDs). Defects in non-lysosomal proteins, transporters, and other lysosomal enzymes are the root cause of these disorders. The most prevalent form of lysosomal storage diseases, known as mucopolysaccharidosis (MPS), occurs when the body is unable to adequately break down mucopolysaccharides. In families from various locations of Pakistan with clinically diagnosed mucopolysaccharidosis type I and type II, the current study sought to find novel genes and pathogenic variants.

Methods: In 14 families, clinical diagnosis revealed 12 cases of mucopolysaccharidosis I and 2 cases of mucopolysaccharidosis II. Whole genome sequencing (WGS) was done on 15 affected individuals to determine the causal variants. Sequencing was also done on 22 unaffected people, including the parents and healthy siblings of the patients. Co-segregation and functional annotation allowed for the identification of potential causal variants.

Results: Ten novel and six previously known variants in the lysosomal storage disorders-related genes IDUA, GALNS, SGSH, GAA, IDS, ALDOB, TRAPPC4, MASP1, SMARCAL, KIAA1109, HERC1, and RRAS2 were discovered through analysis of whole genome sequencing data. Additionally, a novel candidate gene (ABCA5) with traits similar to lysosomal storage disorder has been linked to symptoms that are very similar to those of lysosomal storage disorder in animal models.

Conclusion: The discovery of multigenic inheritance in a number of families emphasizes the need to look for homozygous pathogenic variants in a number of genes, even in highly consanguineous families.

Keywords: MPS, ABCA5, Pakistani families, lysosomal storage disorder, mucopolysaccharidosis, whole genome sequencing