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Of the few reported cases, most present antenatally with a severe phenotype, conveying a poor prognosis. We describe a fetus with severe antenatal\u2010onset\n                    <jats:italic>MRPS22<\/jats:italic>\n                    \u2010related mitochondrial disease and the use of multi\u2010omics in the molecular diagnosis. A primigravida underwent termination of pregnancy following identification of multiple congenital anomalies (hydrops fetalis, microcephaly, corpus callosal agenesis, periventricular cysts and cardiac hypertrophy) on ultrasound at 20\u2009+\u20092\u2009weeks' gestation, confirmed on fetal magnetic resonance imaging. Trio genome sequencing revealed compound heterozygous variants in\n                    <jats:italic>MRPS22<\/jats:italic>\n                    (NM_020191.4: c.509G&gt;A; p.(Arg170His) and c.565C&gt;G; p.(Arg189Gly)). Rapid proteomic analysis demonstrated destabilisation of the small mitoribosomal subunit and combined reduction of OXPHOS complexes, supporting the pathogenicity of the variants. This case consolidates the antenatal phenotype of severe MRPS22\u2010related disease and highlights the importance of considering mitochondrial disease in the differential diagnosis of congenital anomalies, especially hydrops fetalis and corpus callosum anomalies. This study provides evidence for the utility of multi\u2010omic approaches (trio genome sequencing, proteomics) in confirming variant pathogenicity following pregnancy loss, enabling accurate diagnosis, and informing reproductive counselling for affected families.\n                  <\/jats:p>","DOI":"10.1002\/jmd2.70092","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T10:45:47Z","timestamp":1777027547000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antenatal Presentation of\n                    <scp>MRPS22<\/scp>\n                    \u2010Related Mitochondrial Disease Confirmed With Rapid Proteomics"],"prefix":"10.1002","volume":"67","author":[{"given":"Liana N.","family":"Semcesen","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Pharmacology Bio21 Molecular Science and Biotechnology Institute, University of Melbourne  Parkville Victoria 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Children's Research Institute  Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Murdoch Children's Research Institute  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7725-9470","authenticated-orcid":false,"given":"David R.","family":"Thorburn","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute  Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Murdoch Children's Research Institute  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2725-7055","authenticated-orcid":false,"given":"Alison G.","family":"Compton","sequence":"additional","affiliation":[{"name":"Murdoch 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