Molecular characteristics
TMEM94 (Transmembrane Protein 94) gene is located at 17q25 and encodes a nuclear protein with multi-pass membrane domains. The C-terminal region of TMEM94 is evolutionary conserved in many mammalian species and is predicted to be altered in all the affected individuals due to truncating variants. The phenotype of neuro developmental delay, distinct facial dysmorphism, and variable penetrance for cardiac abnormalities in individuals affected by loss-of-function mutations in TMEM94 emphasizes the importance of TMEM94 in neural and cardiovascular development. Mice knockout models of Tmem94 show embryonically lethal phenotype and abnormalities in multiple tissues, including nervous and cardiovascular systems, suggesting the role of this gene in early development.
Mutations and pathophysiology
Mutations in TMEM94 lead to abolishment of the highly conserved C-terminal domain. Stephen et al. (2018) reported TMEM94 (GenBank NM_020812.3) mutations in ten affected individuals from six unrelated families, leading to global developmental delay, intellectual disability, distinct facial dysmorphism, and variable cardiac abnormalities. The following mutations were reported:
- c.2764C>T; p.Arg922* affecting two individuals from an Omani consanguineous family
- c.840del; p.Asp280Glufs*10 affecting three individuals from a consanguineous Qatar family
- c.2635dup; p.Met879Asnfs*18 and c.795-1G>C affecting an individual from a European American non-consanguineous family
- c.2000_2004dup; p.Pro669Alafs*8 affecting an individual from a consanguineous Indian family
- c.4028+5G>A; p.Val1344* affecting two individuals from a Turkish family
- c.3497delA; p.Asn1166Thrfs*84 affecting an individual forma consanguineous Egyptian family