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Disruptions in these pathways can lead to glycosylphosphatidylinositol (GPI) deficiencies, which present with a spectrum of clinical features, including congenital anomalies, dysmorphic features, developmental delay, hypotonia, and epilepsy. Biallelic variants in\n                    <jats:italic>PIGV<\/jats:italic>\n                    , a key mannosyltransferase in GPI biosynthesis, cause Hyperphosphatasia with Impaired Intellectual Development Syndrome 1 (HPMRS1), a rare disorder characterized by hyperphosphatasia, seizures, developmental delay, hypotonia, abnormal MRI findings, and distinct facial dysmorphisms. Fewer than 30 cases have been reported to date. We conducted a case study and literature review; with clinical data obtained from medical records. A 2\u2010year\u2010old female presented with developmental delay, myoclonic epilepsy, hypotonia, and mild facial dysmorphism. Laboratory results showed elevated alkaline phosphatase (899\u2009U\/L) and low pyridoxal 5\u2032\u2010phosphate levels in cerebrospinal fluid (CSF). Brain MRI revealed diffuse cerebral volume loss and ventriculomegaly. Trio genome sequencing identified two\n                    <jats:italic>PIGV<\/jats:italic>\n                    variants: c.1415T&gt;C\u2010p.(Leu472Pro) and c.524T&gt;C\u2010p.(Leu175Pro). Functional studies using\n                    <jats:italic>PIGV<\/jats:italic>\n                    \u2010knockout HEK293 cells transfected with wild\u2010type or mutant\n                    <jats:italic>PIGV<\/jats:italic>\n                    constructs demonstrated reduced GPI\u2010anchored protein (GPI\u2010AP) expression under weaker promoters, indicating impaired enzymatic activity. We report two novel\n                    <jats:italic>PIGV<\/jats:italic>\n                    variants associated with HPMRS1, emphasizing the value of functional assays in variant interpretation. Our findings also highlight the diagnostic relevance of alkaline phosphatase measurement in patients with refractory seizures.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.64220","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T09:10:01Z","timestamp":1755076201000},"page":"171-177","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Characterization of Two Novel Biallelic\n                    <scp>\n                      <i>PIGV<\/i>\n                    <\/scp>\n                    Variants in a Patient With Myoclonic Seizures and Elevated Alkaline Phosphatase: A Case Report"],"prefix":"10.1002","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8302-7705","authenticated-orcid":false,"given":"Matheus Vernet Machado Bressan","family":"Wilke","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology Washington University  St. Louis Missouri USA"},{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Panwar","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes M.","family":"Verheijen","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Pathology University of Utah School of Medicine  Salt Lake City Utah USA"},{"name":"ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Umeshita","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoglycobiology Research Institute for Microbial Diseases, Osaka University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Allen","family":"Thurman","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Virginia Commonwealth University School of Medicine  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Nickels","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kahlen","family":"Darr","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Murakami","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoglycobiology Research Institute for Microbial Diseases, Osaka University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Klee","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3154-4249","authenticated-orcid":false,"given":"Lisa A.","family":"Schimmenti","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6030-1903","authenticated-orcid":false,"given":"Filippo","family":"Pinto e Vairo","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota 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