{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T12:02:51Z","timestamp":1784203371287,"version":"3.55.0"},"reference-count":14,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"THE NATIONAL INSTITUTES OF HEALTH (NIH) MALAYSIA","award":["NMRR ID-21-02426-WU9"],"award-info":[{"award-number":["NMRR ID-21-02426-WU9"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Congenital disorders of glycosylation (CDG) are rare inborn errors of metabolism with multisystemic manifestations. SSR4-CDG is an ultra-rare X-linked subtype caused by pathogenic variants in SSR4, a component of the translocon-associated protein (TRAP) complex essential for protein translocation and N-glycosylation. Case presentation: We report a two-year-old Malaysian male presenting with global developmental delay, central hypotonia, microcephaly with complete agenesis of the corpus callosum, recurrent infections, bilateral vesicoureteral reflux, and failure to thrive. Growth parameters (weight, length, and head circumference) were persistently below the expected percentiles, indicating postnatal growth restriction. Initial metabolic and biochemical investigations for global developmental delay were unremarkable, apart from mild hyperammonemia. Transferrin isoform analysis demonstrated a type I CDG pattern, raising suspicion of a glycosylation defect. Results: Transferrin glycopeptide LC\u2013MS\/MS showed impaired N-glycan occupancy at both glycosylation sites (Asn432 and Asn630), with reduced fully sialylated glycoforms and increased non-glycosylated peptides. Targeted metabolomics using triple quadrupole LC\u2013MS\/MS revealed systemic abnormalities, including elevated arginine and phenylalanine, reduced glutamate, increased lysophosphatidylcholine (C24:0-LPC), and generalized depletion of free and acylcarnitines. Whole-exome sequencing identified a novel hemizygous SSR4 variant (c.98del; p.Pro33LeufsTer23) on the X chromosome, predicted to produce a truncated, nonfunctional protein. Conclusions: This is the first Malaysian patient with SSR4-CDG, comprehensively characterized using a multi-omics diagnostic workflow. The integration of glycoproteomics, metabolomics, and exome sequencing provided a detailed biochemical fingerprint that expands the clinical, genetic, and metabolic spectrum of SSR4-CDG and demonstrates the diagnostic and translational value of multi-omics approaches in inborn errors of metabolism.<\/jats:p>","DOI":"10.3390\/metabo15120786","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T15:30:07Z","timestamp":1765207807000},"page":"786","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multi-Omics Characterization of a Novel SSR4 Variant in Congenital Disorders of Glycosylation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6818-7973","authenticated-orcid":false,"given":"Nurulamin","family":"Abu Bakar","sequence":"first","affiliation":[{"name":"Centre of Diagnostics, Therapeutics and Investigative Studies (CODTIS), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3157-8819","authenticated-orcid":false,"given":"Nurul Izzati","family":"Hamzan","sequence":"additional","affiliation":[{"name":"Special Protein Unit, Specialized Diagnostic Centre, Institute for Medical Research, National Institutes of Health, Jalan Pahang, Kuala Lumpur 50588, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9337-0163","authenticated-orcid":false,"given":"Elyssa Milus","family":"Majawit","sequence":"additional","affiliation":[{"name":"Department of Paediatric, Sabah Women and Child Hospital (SWACH), Kota Kinabalu 88996, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2800-4188","authenticated-orcid":false,"given":"Siti Nurwani","family":"Ahmad Ridzuan","sequence":"additional","affiliation":[{"name":"Special Protein Unit, Specialized Diagnostic Centre, Institute for Medical Research, National Institutes of Health, Jalan Pahang, Kuala Lumpur 50588, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor Hafizah","family":"Hassan","sequence":"additional","affiliation":[{"name":"Special Protein Unit, Specialized Diagnostic Centre, Institute for Medical Research, National Institutes of Health, Jalan Pahang, Kuala Lumpur 50588, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5529-5115","authenticated-orcid":false,"given":"Anasufiza","family":"Habib","sequence":"additional","affiliation":[{"name":"Specialized Diagnostic Centre, Institute for Medical Research, National Institutes of Health, Jalan Pahang, Kuala Lumpur 50588, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2396-1686","authenticated-orcid":false,"given":"Lock-Hock","family":"Ngu","sequence":"additional","affiliation":[{"name":"Department of Genetic, Kuala Lumpur Hospital, Jalan Pahang, Kuala Lumpur 50586, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108476","DOI":"10.1016\/j.ymgme.2024.108476","article-title":"Clinical and biochemical footprints of congenital disorders of glycosylation: Proposed nosology","volume":"142","author":"Ng","year":"2024","journal-title":"Mol. 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