{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T07:07:53Z","timestamp":1789456073116,"version":"build-2803163510"},"reference-count":10,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The molecular determinants of phenotypic severity in red cell enzymopathies are often obscured by the disconnect between coding sequence variants and their regulatory landscapes. Here we present a single\u2010patient molecular case study that uses an integrative multi\u2010omic approach\u2014combining short\u2010read WGS, PacBio HiFi long\u2010read sequencing, native CpG methylation profiling, and Iso\u2010Seq full\u2010length transcriptomics\u2014to characterize a severe, transfusion\u2010dependent hemolytic anaemia. We identified a compound heterozygous state in the glucose\u20106\u2010phosphate isomerase (GPI) gene, with no wild\u2010type allele present. One allele (Haplotype 1) carried a missense variant (p.His191Arg); the other (Haplotype 2) carried a distinct missense variant, c.1414C&gt;T (p.Arg472Cys), previously reported as biochemically unstable. Long\u2010read phasing placed the two variants in trans. Allele\u2010resolved transcript counts showed a directionally consistent but statistically non\u2010significant trend toward higher expression of Haplotype 2 across two Iso\u2010Seq replicates. Notably, the c.1414C&gt;T transition abolishes a local CpG dinucleotide; in a small number of haplotype\u20102 reads spanning this position, the corresponding cytosine on the wild\u2010type\/Haplotype\u20101 background was methylated. We did not measure GPI protein abundance, enzymatic activity, or stability in this patient, and we do not establish that methylation at this site regulates GPI transcription. On the basis of these correlative observations in a single patient, we propose\u2014as a hypothesis for future testing\u2014that a coding variant might simultaneously perturb protein stability and disrupt a local epigenetic mark, and we outline the experiments required to test whether such a dual effect contributes to disease. This case illustrates the value of integrative long\u2010read multi\u2010omics for generating mechanistic hypotheses about variants of uncertain significance, while underscoring that causal claims require dedicated functional validation.<\/jats:p>","DOI":"10.1111\/jcmm.71338","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:40:31Z","timestamp":1789134031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Long\u2010Read Multi\u2010Omics of a Patient With\n                    <scp>GPI<\/scp>\n                    Deficiency: A Molecular Case Study of a Candidate Dual\u2010Effect\n                    <scp>GPI<\/scp>\n                    Variant"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1100-2138","authenticated-orcid":false,"given":"Ireneusz","family":"Stolarek","sequence":"first","affiliation":[{"name":"Institute of Bioorganic Chemistry Polish Academy of Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6690-211X","authenticated-orcid":false,"given":"Joanna","family":"Delimata\u2010Raczek","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry Polish Academy of Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7096-0128","authenticated-orcid":false,"given":"Natalia","family":"Koralewska","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry Polish Academy of Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaudia","family":"Sikora","sequence":"additional","affiliation":[{"name":"Ludwik Rydygier Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Toru\u0144  Bydgoszcz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Rakoczy","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry Polish Academy of Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8809-335X","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Marcinkowska\u2010Swojak","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry Polish Academy of Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9803-6877","authenticated-orcid":false,"given":"Luiza","family":"Handschuh","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry Polish Academy of Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4178-7837","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Czy\u017c","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Bydgoszcz University of Science and Technology  Bydgoszcz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6392-0192","authenticated-orcid":false,"given":"Marek","family":"Figlerowicz","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry Polish Academy of Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1053\/beha.1999.0059"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/Nejm198701293160506"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00441768"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00320579"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2016.06.002"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13256-024-04466-7"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2017.04.003"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167\u20104838(89)90286\u20100"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102434\u20102"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V122.21.947.947"}],"container-title":["Journal 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