Severe microcephaly

Gene: TM2D3

Green List (high evidence)

Comment on list classification: There are three unrelated patients reported with severe microcephaly (OFC beyond -3 SD). Hence, this gene can be promoted to green rating in the next GMS update.

Created: 2 Jan 2026, 9:45 p.m. | Last Modified: 2 Jan 2026, 9:45 p.m.

Panel Version: 8.25

PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Microcephaly was severe in three of four patients (OFC beyond -3 SD), while OFC is -2.5 SD in the fourth patient. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature

Created: 2 Jan 2026, 9:43 p.m. | Last Modified: 2 Jan 2026, 9:45 p.m.

Panel Version: 8.25

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurocardiorenal malformation syndrome, OMIM:621379

Publications

• 40449487