biostudies-literatureChapman KANational Institute of Neurological Disorders and StrokeNIMH NIH HHSNINDS NIH HHSNational Institute of Mental HealthNational Institutes of HealthUniversity of Arizona2381-2401https://www.ebi.ac.uk/biostudies/studies/S-EPMC12440709biostudies-literatureUnknown112(10)Transmembrane protein 184B (TMEM184B) is an endosomal 7-pass transmembrane protein with evolutionarily conserved roles in synaptic structure and axon degeneration. We report six pediatric cases who have de novo heterozygous variants in TMEM184B; five individuals harbor a rare missense variant, and one individual has an mRNA splice site change. This cohort is unified by overlapping neurodevelopmental deficits including developmental delay, corpus callosum hypoplasia, seizures, and/or microcephaly. TMEM184B is predicted to contain a pore domain wherein four of five human disease-associated missense variants cluster. Structural modeling suggests that all missense variants alter TMEM184B protein stability. To understand the contribution of TMEM184B to neural development in vivo, we knocked dowAmerican journal of human geneticsPathogenic variants in TMEM184B cause a neurodevelopmental syndrome associated with alteration of metabolic signaling.PMC12440709R01 MH106826R01 NS105680Muss CPowell ATKeren BSofocleous CChapman KAPond KWFryssira HCorreia SPAccogli ABerger SIDavis EEKellaris GTraeger-Synodinos JStodberg TTsoutsou ESciruicchio VKodiparthi SVMarinakis NMSalpietro VStriano PHeron DSirimulla SBhattacharya MRCWhite HGUllah FYahiku ZAKhan SfalsePathogenic variants in TMEM184B cause a neurodevelopmental syndrome associated with alteration of metabolic signaling.Transmembrane protein 184B (TMEM184B) is an endosomal 7-pass transmembrane protein with evolutionarily conserved roles in synaptic structure and axon degeneration. We report six pediatric cases who have de novo heterozygous variants in TMEM184B; five individuals harbor a rare missense variant, and one individual has an mRNA splice site change. This cohort is unified by overlapping neurodevelopmental deficits including developmental delay, corpus callosum hypoplasia, seizures, and/or microcephaly. TMEM184B is predicted to contain a pore domain wherein four of five human disease-associated missense variants cluster. Structural modeling suggests that all missense variants alter TMEM184B protein stability. To understand the contribution of TMEM184B to neural development in vivo, we knocked dow2025-01-01T00:00:00Z2025 Oct2026-06-04T11:00:33.08Z2026-05-08T03:10:51.717ZS-EPMC124407094088518510.1016/j.ajhg.2025.08.004