Purpose:
To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder.
Methods:
A combination of exome sequencing and gene matching tools was used
to identify pathogenic variants in 17 individuals. Quantitative reverse
transcription polymerase chain reaction (RT-qPCR) and subcellular
localization studies were used to characterize gene expression profile
and localization.
Results:
Biallelic variants in the TMEM222 gene were identified in 17
individuals from nine unrelated families, presenting with intellectual
disability and variable other features, such as aggressive behavior, shy
character, body tremors, decreased muscle mass in the lower
extremities, and mild hypotonia. We found relatively high TMEM222
expression levels in the human brain, especially in the parietal and
occipital cortex. Additionally, subcellular localization analysis in
human neurons derived from induced pluripotent stem cells (iPSCs)
revealed that TMEM222 localizes to early endosomes in the synapses of
mature iPSC-derived neurons.
Conclusion:
Our findings support a role for TMEM222 in brain development and
function and adds variants in the gene TMEM222 as a novel underlying
cause of an autosomal recessive neurodevelopmental disorder.