{"doi":"10.1038/s42003-025-08059-y","title":"Is Gauchian genotyping of GBA1 variants reliable?","abstract":"Gaucher disease (GD) results from biallelic pathogenic variants in the gene GBA1 , which encodes the lysosomal enzyme glucocerebrosidase (E.C.3.2.1.45). Over 500 pathogenic variants in GBA1 , located on chromosome 1q21, have been identified in patients with GD 1 , 2 . Variants in GBA1 are also the most common known genetic risk factor for Parkinson disease (PD) and dementia with Lewy bodies (DLB) 3 , 4 , 5 , 6 . The presence of a highly homologous GBA1 pseudogene, GBAP1 , located approximately 16 kb downstream from the gene 7 , complicates variant detection and sequence analyses, as highly homologous pseudogenes increase the frequency of nonequal pairing of chromosomes, resulting in complex recombinant alleles 8 , 9 , 10 (Fig. 1 ). While GBAP1 is 96% homologous to GBA1 in exonic regions, this sequence similarity increases to ~98% between intron 8 to the 3’untranslated region (UTR), where a 55 bp deletion in exon 9 is the major exonic difference 7 , 11 . Contiguous to GBA1 and GBAP1 are the gene MTX1 and its pseudogene MTX1P , which also tend to generate DNA rearrangements 12 , 13 (Fig. 1 ). Some Gaucher-related variants are present in GBAP1 11 , 14 . Furthermore, gene-pseudogene DNA rearrangements comprise a significant proportion of mutant GBA1 alleles, and such alterations have been detected at different sites between intron 2 to the 3’UTR 1 , 15 , 16 . Over twenty different recombinant alleles have been described 17 , 18 , 19 , with Rec NciI , RecTL, and RecTL+55 bp being the most common. Direct Sanger sequencing, quantitative real-time PCR, Southern blotting, and lately, WGS have been utilized to detect the most common recombinant alleles 1 , 17 , 20 both for the diagnosis of GD and PD research 10 , 21 , 22 , 23 . Fig. 1: Two nearby genes, GBA1 and MTX1 and their pseudogenes. A Illustration of a portion of chromosome 1q21 demonstrating the physical relationship between the genes GBA1 and MTX1 , and their homologous pseudogenes with sense and antisense orientation shown. B Schematic presentation of a reciprocal cross-over between homologous regions resulting in two possible gene rearrangements: (i) a fusion between the gene and its pseudogene resulting in a deletion of the intergenic region, and (ii) a recombination resulting in a third sequence containing a partial duplication of the pseudogene and several duplicated exons from the gene sequence. The two slanted vertical lines indicate regions omitted in the diagram. The X indicates the site of recombination. del deletion, bp base pairs. Full size image","journal":"Communications Biology","year":2025,"id":521154,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9601,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":892091,"name":"Jens Lichtenberg","orcid":"0000-0002-0023-4937","position":1,"is_corresponding":false},{"id":878509,"name":"Ellen Hertz","orcid":"0000-0002-0916-3557","position":2,"is_corresponding":false},{"id":305686,"name":"Ellen Sidransky","orcid":"0000-0002-3019-8500","position":3,"is_corresponding":false},{"id":305683,"name":"Nahid Tayebi","orcid":"0000-0002-1007-4957","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-19T02:49:32.958846Z","pmid":"40346301","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}