TY - JOUR

T1 - Identifying the genetic causes of phenotypically diagnosed Pakistani mucopolysaccharidoses patients by whole genome sequencing

AU - Gul, Rutaba

AU - Firasat, Sabika

AU - Schubert, Mikkel

AU - Ullah, Asmat

AU - Peña, Elionora

AU - Thuesen, Anne C.B.

AU - Hussain, Mulazim

AU - Staeger, Frederik F.

AU - Gjesing, Anette P.

AU - Albrechtsen, Anders

AU - Hansen, Torben

N1 - Publisher Copyright: Copyright © 2023 Gul, Firasat, Schubert, Ullah, Peña, Thuesen, Hussain, Staeger, Gjesing, Albrechtsen and Hansen.

PY - 2023

Y1 - 2023

N2 - Background: Lysosomal storage disorders (LSDs) are a group of inherited metabolic diseases, which encompass more than 50 different subtypes of pathologies. These disorders are caused by defects in lysosomal enzymes, transporters, and other non-lysosomal proteins. Mucopolysaccharidosis (MPS) is the most common subgroup of lysosomal storage disorders in which the body is unable to properly breakdown mucopolysaccharides. 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. Methods: Clinical diagnosis identified 12 with mucopolysaccharidosis I and 2 with mucopolysaccharidosis II in 14 families and whole genome sequencing (WGS) was performed to identify the causative variations in 15 affected individuals. Twenty-two unaffected individuals including parents or normal siblings of patients were also sequenced. Putative causal variants were identified by co-segregation and functional annotation. Results: Analysis of whole genome sequencing data revealed ten novel and six previously reported variants in lysosomal storage disorders-associated genes (IDUA, GALNS, SGSH, GAA, IDS, ALDOB, TRAPPC4, MASP1, SMARCAL, KIAA1109, HERC1, RRAS2) and a novel candidate gene (ABCA5) for lysosomal storage disorder-like phenotypes, which has previously been associated with symptoms strongly related with lysosomal storage disorder in animal models. Conclusion: Multigenic inheritance was found in several families highlighting the importance of searching for homozygous pathogenic variants in several genes also in families with a high degree of consanguinity.

AB - Background: Lysosomal storage disorders (LSDs) are a group of inherited metabolic diseases, which encompass more than 50 different subtypes of pathologies. These disorders are caused by defects in lysosomal enzymes, transporters, and other non-lysosomal proteins. Mucopolysaccharidosis (MPS) is the most common subgroup of lysosomal storage disorders in which the body is unable to properly breakdown mucopolysaccharides. 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. Methods: Clinical diagnosis identified 12 with mucopolysaccharidosis I and 2 with mucopolysaccharidosis II in 14 families and whole genome sequencing (WGS) was performed to identify the causative variations in 15 affected individuals. Twenty-two unaffected individuals including parents or normal siblings of patients were also sequenced. Putative causal variants were identified by co-segregation and functional annotation. Results: Analysis of whole genome sequencing data revealed ten novel and six previously reported variants in lysosomal storage disorders-associated genes (IDUA, GALNS, SGSH, GAA, IDS, ALDOB, TRAPPC4, MASP1, SMARCAL, KIAA1109, HERC1, RRAS2) and a novel candidate gene (ABCA5) for lysosomal storage disorder-like phenotypes, which has previously been associated with symptoms strongly related with lysosomal storage disorder in animal models. Conclusion: Multigenic inheritance was found in several families highlighting the importance of searching for homozygous pathogenic variants in several genes also in families with a high degree of consanguinity.

KW - ABCA5

KW - lysosomal storage disorder

KW - mucopolysaccharidosis

KW - Pakistani families

KW - whole genome sequencing

U2 - 10.3389/fgene.2023.1128850

DO - 10.3389/fgene.2023.1128850

M3 - Journal article

C2 - 37091798

AN - SCOPUS:85153064328

VL - 14

JO - Frontiers in Genetics

JF - Frontiers in Genetics

SN - 1664-8021

M1 - 1128850

ER -