Search

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.

Purpose: The interpretation of genetic variants after genome-wide analysis is complex in heterogeneous disorders such as intellectual disability (ID). We investigate whether algorithms can be used to detect if a facial gestalt is present for three novel ID syndromes and if these techniques can help interpret variants of uncertain significance., Methods: Facial features were extracted from photos of ID patients harboring a pathogenic variant in three novel ID genes (PACS1, PPM1D, and PHIP) using algorithms that model human facial dysmorphism, and facial recognition. The resulting features were combined into a hybrid model to compare the three cohorts against a background ID population., Results: We validated our model using images from 71 individuals with Koolen-de Vries syndrome, and then show that facial gestalts are present for individuals with a pathogenic variant in PACS1 (p = 8 × 10 -4 ), PPM1D (p = 4.65 × 10 -2 ), and PHIP (p = 6.3 × 10 -3 ). Moreover, two individuals with a de novo missense variant of uncertain significance in PHIP have significant similarity to the expected facial phenotype of PHIP patients (p < 1.52 × 10 -2 )., Conclusion: Our results show that analysis of facial photos can be used to detect previously unknown facial gestalts for novel ID syndromes, which will facilitate both clinical and molecular diagnosis of rare and novel syndromes.