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The highly conserved biosynthesis of GPI-APs involves precise steps with at least 21 genes, categorized as PIG and PGAP genes. Pathogenic variants in these genes are linked to human diseases, highlighting the importance of each biosynthesis step. PGAP2 stands out among these genes due to its association with an expanded clinical spectrum of neurodevelopmental disorder (NDD) phenotypes with biallelic pathogenic variants. We present four patients from two families, one consanguineous and the other nonconsanguineous, each displaying distinct clinical presentations, including intellectual disability, hyperphosphatasia, hearing impairment, and epilepsy, as well as craniofacial and digital anomalies. Genetic analyses revealed homozygous and novel compound heterozygous missense variants in PGAP2 in four affected individuals, confirming the molecular diagnosis of hyperphosphatasia with impaired intellectual development syndrome 3 (HPMRS3). Importantly, the three amino acids affected by missense variants exhibit complete conservation in 10 vertebrate species, illuminating their crucial role in the gene\u2019s functionality. Protein modeling provided additional evidence for the pathogenicity of the three substitutions, demonstrating their detrimental impact on protein folding and putative protein-protein interactions, ultimately leading to impaired protein function. The four patients in our study displayed common phenotypic features, such as brachydactyly, camptodactyly, and syndactyly, which have not been previously documented in individuals with PGAP2 variants. Notably, the occurrence of macrocephaly in two affected brothers from a consanguineous Pakistani family represents a novel finding. These previously unreported digital anomalies, along with macrocephaly and the identification of novel compound heterozygous variants, contribute to the expansion of the phenotypic and genotypic spectrum of HPMRS3 associated with PGAP2 variants.<\/jats:p>","DOI":"10.1155\/2024\/5518289","type":"journal-article","created":{"date-parts":[[2024,1,6]],"date-time":"2024-01-06T00:23:49Z","timestamp":1704500629000},"page":"1-13","source":"Crossref","is-referenced-by-count":1,"title":["Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)"],"prefix":"10.1155","volume":"2024","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9689-3111","authenticated-orcid":true,"given":"Seda","family":"Susgun","sequence":"first","affiliation":[{"name":"Department of Biology, Chungnam National University, Daejeon 34134, Republic of Korea"},{"name":"Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3520-8015","authenticated-orcid":true,"given":"Afif","family":"Ben-Mahmoud","sequence":"additional","affiliation":[{"name":"Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5640-810X","authenticated-orcid":true,"given":"Franz","family":"R\u00fcschendorf","sequence":"additional","affiliation":[{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1784-8975","authenticated-orcid":true,"given":"Bonsu","family":"Ku","sequence":"additional","affiliation":[{"name":"Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1589-7626","authenticated-orcid":true,"given":"Syeda Iqra","family":"Hussain","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering, Kohat University of Science & Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4522-4486","authenticated-orcid":true,"given":"Solveig","family":"Schulz","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Humangenetik, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-6513","authenticated-orcid":true,"given":"Oliver","family":"Puk","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Humangenetik, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1573-861X","authenticated-orcid":true,"given":"Saskia","family":"Biskup","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Humangenetik, T\u00fcbingen, Germany"},{"name":"Center for Genomics and Transcriptomics (CeGaT), T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D. 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