Identification of genetic variants associated with a wide spectrum of phenotypes clinically diagnosed as Sanfilippo and Morquio syndromes using whole genome sequencing

Frontiers in Genetics

Genetics

Kiran Afshan¹  Sabika Firasat¹  Muhammad Tufail¹  Muhammad Saqib²  Rutaba Gul³  Annete P. Gjesing⁴  Mikkel Schubert⁴  Asmat Ullah⁴  Anne C. B. Thuesen⁴  Torben Hansen⁴  Elionora Peña⁴  Mulazim Hussain⁵ 

[1] Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan;Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan;Department of Zoology, University of Lakki Marwat, Lakki Marwat, Khyber Pakhtunkhwa, Pakistan;Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan;Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;The Children Hospital, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan;

关键词: Sanfilippo syndrome;    Morquio syndrome;    Pakistani families;    whole genome sequencing;    VWA3B;   

DOI  :  10.3389/fgene.2023.1254909

 received in 2023-07-12, accepted in 2023-08-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

Mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders (LSDs). MPSs are caused by excessive accumulation of mucopolysaccharides due to missing or deficiency of enzymes required for the degradation of specific macromolecules. MPS I-IV, MPS VI, MPS VII, and MPS IX are sub-types of mucopolysaccharidoses. Among these, MPS III (also known as Sanfilippo) and MPS IV (Morquio) syndromes are lethal and prevalent sub-types. This study aimed to identify causal genetic variants in cases of MPS III and MPS IV and characterize genotype-phenotype relations in Pakistan. We performed clinical, biochemical and genetic analysis using Whole Genome Sequencing (WGS) in 14 Pakistani families affected with MPS III or MPS IV. Patients were classified into MPS III by history of aggressive behaviors, dementia, clear cornea and into MPS IV by short trunk, short stature, reversed ratio of upper segment to lower segment with a short upper segment. Data analysis and variant selections were made based on segregation analysis, examination of known MPS III and MPS IV genes, gene function, gene expression, the pathogenicity of variants based on ACMG guidelines and in silico analysis. In total, 58 individuals from 14 families were included in the present study. Six families were clinically diagnosed with MPS III and eight families with MPS IV. WGS revealed variants in MPS-associated genes including NAGLU, SGSH, GALNS, GNPTG as well as the genes VWA3B, BTD, and GNPTG which have not previously associated with MPS. One family had causal variants in both GALNS and BTD. Accurate and early diagnosis of MPS in children represents a helpful step for designing therapeutic strategies to protect different organs from permanent damage. In addition, pre-natal screening and identification of genetic etiology will facilitate genetic counselling of the affected families. Identification of novel causal MPS genes might help identifying new targeted therapies to treat LSDs.

【 授权许可】

Unknown   
Copyright © 2023 Gul, Firasat, Schubert, Ullah, Peña, Thuesen, Gjesing, Hussain, Tufail, Saqib, Afshan and Hansen.