Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities.

ABSTRACT: We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. TM2D3 encodes a transmembrane protein present in many tissues, with a higher abundance in the central nervous system, but little is known about its function and cell localization. Here, by using chemical and genetically encoded probes in SNB75 cells, we show that TM2D3 is an endoplasmic reticulum (ER) protein. Further analysis on SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele revealed an impact of

SUBMITTER: Gabillard-Lefort C 

PROVIDER: S-EPMC12256896 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature