{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:57:27Z","timestamp":1776855447556,"version":"3.51.2"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T00:00:00Z","timestamp":1680652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Analysis of whole genome sequencing data revealed ten novel and six previously reported variants in lysosomal storage disorders-associated genes (<jats:italic>IDUA, GALNS, SGSH, GAA, IDS<\/jats:italic>, <jats:italic>ALDOB, TRAPPC4, MASP1, SMARCAL, KIAA1109, HERC1, RRAS2<\/jats:italic>) and a novel candidate gene (<jats:italic>ABCA5<\/jats:italic>) for lysosomal storage disorder-like phenotypes, which has previously been associated with symptoms strongly related with lysosomal storage disorder in animal models.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> 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.<\/jats:p>","DOI":"10.3389\/fgene.2023.1128850","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T05:28:30Z","timestamp":1680672510000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Identifying the genetic causes of phenotypically diagnosed Pakistani mucopolysaccharidoses patients by whole genome sequencing"],"prefix":"10.3389","volume":"14","author":[{"given":"Rutaba","family":"Gul","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabika","family":"Firasat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikkel","family":"Schubert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asmat","family":"Ullah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elionora","family":"Pe\u00f1a","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne C. B.","family":"Thuesen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mulazim","family":"Hussain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederik F.","family":"Staeger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anette P.","family":"Gjesing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anders","family":"Albrechtsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Torben","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1007\/s10545-007-0551-9","article-title":"Enzyme replacement therapy in 12 patients with MPS I\u2013H\/S with homozygous p. Leu490Pro mutation","volume":"30","author":"Arora","year":"2007","journal-title":"J. Inherit. Metab. Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/11905","article-title":"Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency","volume":"22","author":"Brooks-Wilson","year":"1999","journal-title":"Nat. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1016\/j.ajhg.2019.04.013","article-title":"Activating mutations of RRAS2 are a rare cause of Noonan syndrome","volume":"104","author":"Capri","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: an ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"giab008","DOI":"10.1093\/gigascience\/giab008","article-title":"Twelve years of SAMtools and BCFtools","volume":"10","author":"Danecek","year":"2021","journal-title":"Gigascience"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e1004333","DOI":"10.1371\/journal.pgen.1004333","article-title":"Mutations in the cholesterol transporter gene ABCA5 are associated with excessive hair overgrowth","volume":"10","author":"DeStefano","year":"2014","journal-title":"PLoS Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","article-title":"MultiQC: Summarize analysis results for multiple tools and samples in a single report","volume":"32","author":"Ewels","year":"2016","journal-title":"Bioinformatics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"8390","DOI":"10.1093\/nar\/17.20.8390","article-title":"A simple and efficient non-organic procedure for the isolation of genomic DNA from blood","volume":"17","author":"Grimberg","year":"1989","journal-title":"Nucleic Acids Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1111\/cga.12354","article-title":"IDUA gene mutations in mucopolysaccharidosis type\u20101 patients from two Pakistani inbred families","volume":"60","author":"Gul","year":"2020","journal-title":"Congenit. Anom."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.2298\/gensr2103017g","article-title":"Neurological manifestations in Pakistani lysosomal storage disorders patients and molecular characterization of Gaucher disease","volume":"53","author":"Gul","year":"2021","journal-title":"Genetika"},{"key":"B11","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1002\/mgg3.37","article-title":"Next\u2010generation DNA sequencing of hexa: A step in the right direction for carrier screening","volume":"1","author":"Hoffman","year":"2013","journal-title":"Mol. Genet. Genomic"},{"key":"B12","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1017\/s0021932098002612","article-title":"The prevalence and demographic characteristics of consanguineous marriages in Pakistan","volume":"30","author":"Hussain","year":"1998","journal-title":"J. Biosoc. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e29","DOI":"10.1093\/brain\/awaa046","article-title":"Recurrent bi-allelic splicing variant c.454+ 3A>G in TRAPPC4 is associated with progressive encephalopathy and muscle involvement","volume":"143","author":"Kaur","year":"2020","journal-title":"Brain"},{"key":"B15","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.beem.2014.08.004","article-title":"Epidemiology and diagnosis of lysosomal storage disorders; challenges of screening","volume":"29","author":"Kingma","year":"2015","journal-title":"Best. Pract. Res. Clin. Endocrinol. Metab."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1002\/jimd.12431","article-title":"MPS I: Early diagnosis, bone disease and treatment, where are we now?","volume":"44","author":"Kingma","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"232640981666937","DOI":"10.1177\/2326409816669376","article-title":"The role of Next-Generation Sequencing in the diagnosis of lysosomal storage disorders","volume":"4","author":"Komlosi","year":"2016","journal-title":"J. inborn errors Metab. screen"},{"key":"B18","doi-asserted-by":"publisher","first-page":"4138","DOI":"10.1128\/MCB.25.10.4138-4149.2005","article-title":"ABCA5 resides in lysosomes, and ABCA5 knockout mice develop lysosomal disease-like symptoms","volume":"25","author":"Kubo","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"B19","article-title":"Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM","volume-title":"arXiv","author":"Li","year":"2013"},{"key":"B20","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1136\/hrt.2005.063818","article-title":"The heart in Anderson-Fabry disease and other lysosomal storage disorders","volume":"93","author":"Linhart","year":"2007","journal-title":"Heart"},{"key":"B21","doi-asserted-by":"publisher","first-page":"jcs221739","DOI":"10.1242\/jcs.221739","article-title":"Lysosomal storage disorders\u2013challenges, concepts and avenues for therapy: Beyond rare diseases","volume":"132","author":"Marques","year":"2019","journal-title":"J. Cell Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"B24","first-page":"119","article-title":"Diagnostic methods for lysosomal storage disease","volume":"7","author":"Mokhtariye","year":"2019","journal-title":"Rep. Biochem. Mol. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1111\/cge.12634","article-title":"Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability","volume":"88","author":"Ortega-Recalde","year":"2015","journal-title":"Clin. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1146\/annurev-med-122313-085916","article-title":"Lysosomal storage diseases: From pathophysiology to therapy","volume":"66","author":"Parenti","year":"2015","journal-title":"Annu. Rev. Med."},{"key":"B27","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1007\/978-3-030-67727-5_64","article-title":"The mucopolysaccharidoses","volume-title":"Physician's guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases","author":"Parenti","year":"2022"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1111\/ced.15128","article-title":"Exome sequencing reveals the first intragenic deletion in ABCA5 underlying autosomal recessive hypertrichosis","volume":"47","author":"Raza","year":"2020","journal-title":"Clin. Exp. Dermatol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/gim.2015.148","article-title":"Clinical application of whole-exome sequencing across clinical indications","volume":"18","author":"Retterer","year":"2016","journal-title":"Genet. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2020","journal-title":"Genet. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1038\/nprot.2014.063","article-title":"Characterization of ancient and modern genomes by SNP detection and phylogenomic and metagenomic analysis using PALEOMIX","volume":"9","author":"Schubert","year":"2014","journal-title":"Nat. Protoc."},{"key":"B32","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41434-019-0113-4","article-title":"Neonatal nonviral gene editing with the CRISPR\/Cas9 system improves some cardiovascular, respiratory, and bone disease features of the mucopolysaccharidosis I phenotype in mice","volume":"27","author":"Schuh","year":"2029","journal-title":"Gene Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1093\/nar\/29.1.308","article-title":"dbSNP: the NCBI database of genetic variation","volume":"29","author":"Sherry","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1002\/humu.1380060206","article-title":"Mucopolysaccharidosis type II (hunter disease): Identification and characterization of eight point mutations in the iduronate\u20102\u2010sulfatase gene in Japanese patients","volume":"6","author":"Sukegawa","year":"1995","journal-title":"Hum. Mutat."},{"key":"B35","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/humu.1380060111","article-title":"Four novel mutations underlying mild or intermediate forms of \u03b1\u2010L\u2010iduronidase deficiency (MPS IS and MPS IH\/S)","volume":"6","author":"Tieu","year":"1995","journal-title":"Hum. Mutat."},{"key":"B36","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1093\/hmg\/4.4.741","article-title":"Mucopolysaccharidosis type IVA: Identification of six novel mutations among non-Japanese patients","volume":"4","author":"Tomatsu","year":"1995","journal-title":"Hum. Mol. Genet."},{"key":"B37","doi-asserted-by":"publisher","first-page":"458","DOI":"10.3906\/biy-1607-81","article-title":"Identification and in silico analysis of GALNS mutations causing Morquio A syndrome in eight consanguineous families","volume":"41","author":"Ullah","year":"2017","journal-title":"Turk J. Bio"},{"key":"B38","first-page":"90","article-title":"Whole exome sequencing as a diagnostic tool for genetic disorders in Pakistan","volume":"57","author":"Umair","year":"2018","journal-title":"Pak J. Med. Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1007\/s12041-017-0868-6","article-title":"Ellis-van Creveld syndrome and profound deafness resulted by sequence variants in the EVC\/EVC2 and TMC1 genes","volume":"96","author":"Umair","year":"2017","journal-title":"J. Genet."},{"key":"B40","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1093\/brain\/awz374","article-title":"Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability","volume":"143","author":"Van Bergen","year":"2020","journal-title":"Brain"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1093\/hmg\/6.9.1573","article-title":"Novel mutations in sanfilippo A syndrome: Implications for enzyme function","volume":"6","author":"Weber","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"B42","doi-asserted-by":"publisher","first-page":"684067","DOI":"10.3389\/fgene.2021.684067","article-title":"Next-Generation Sequencing analysis of GBA1: The challenge of detecting complex recombinant alleles","volume":"12","author":"Woo","year":"2021","journal-title":"Front. Genet."},{"key":"B43","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1001\/jama.2013.281053","article-title":"World medical association declaration of Helsinki: Ethical principles for medical research involving human subjects","volume":"310","year":"2013","journal-title":"Jama"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1128850\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T05:28:36Z","timestamp":1680672516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1128850\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,5]]},"references-count":43,"alternative-id":["10.3389\/fgene.2023.1128850"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1128850","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,5]]},"article-number":"1128850"}}