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Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder



To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder.


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.


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.


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.

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Fig. 1: Homozygous variants in TMEM222 lead to intellectual disability.
Fig. 2: Expression of TMEM222 in selected human tissues.
Fig. 3: Human TMEM222 is highly expressed in dendrites of mature iNeurons and partially colocalizes with postsynaptic and early endosomal markers.

Data availability

The TMEM222 variant data were submitted to LOVD database ( hosted at Leiden University Medical Center, the Netherlands. Accession numbers are available in Table 1. Additional data and materials, such as primer sequences and Sanger sequencing electropherograms, are available upon request.


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We are grateful to the families who have participated in this study. This work was supported the EU FP7 Large-Scale Integrating Project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995) (to H.v.B.), an ERC grant (to S.E.A.), National Institute on Neurological Disorders and Stroke (R01NS107428) (to Sheikh Riazuddin), the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898, Jordan’s Guardian Angels and the Brotman Baty Institute (to G.M.M.) and state assignment of Ministry of Science and Higher Education of the Russian Federation for RCMG. D.L.P. is recipient of a CAPES Fellowship (99999.013311/2013-01). Part of this work was supported by Higher Education Commission of Pakistan (NRPU project number 10700 to M.S.).

Author information




Conceptualization: D.L.P., M.A.F., P.M., H.v.B., Sheikh Riazuddin. Data curation: D.L.P., A.P.M.d.B., H.v.B. Formal analysis: D.L.P., H.V., H.v.B., N.N.K. Methodology: D.L.P., A.P.M.d.B., H.V., K.L., F.F., N.F., O.A.L., P.N., P.M., M.H., S.v.H., A.K.B., P.H., Z.T., S.Z., M.S.F., J.H.M.S.H., M.S., L.D.K., H.T.B., L.R.F., J.C., A.P., J.P., N.A.D., A.L.C., V.S.S., A.T.M., N.N.K., H.H., F.A.S., Z.M.A., S.H., M.Y., M.A., M.S. G.R., E.E., A.T.S., S.B., G.M.M. Supervision: M.A.F.F., R.P., Saima Riazuddin, Sheikh Riazuddin, F.P., A.V.L., S.E.A., M.A.F., H.v.B. Validation: D.L.P., H.v.B. Visualization: D.L.P., P.M., H.v.B. Writing—original draft: D.L.P., H.v.B. Writing—review & editing: D.L.P., M.A.F.F., R.P., Saima Riazuddin, Sheikh Riazuddin, F.P., A.K.B., A.V.L., S.E.A., M.A.F., H.v.B.

Corresponding author

Correspondence to Hans van Bokhoven.

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Individuals were identified in different centers worldwide in diagnostic or research settings approved by the respective institutional review boards: the Institutional Review Board Commissie Mensgebonden Onderzoek Regio Arnhem-Nijmegen, the Netherlands; Institutional Review Board at University of Maryland School of Medicine, Baltimore, Maryland, USA; Institutional Review Board, Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan; Institution Board of Jordan University Hospital, Amman, Jordan; Bioethics Committee of the University Hospitals and the Canton of Geneva, Switzerland; Ethics Committee of the Research Centre for Medical Genetics, Moscow, Russia; Persian BayanGene Research and Training Center Ethics Committee, Shiraz, Iran; institutional review boards of the Hanover Medical School the Children’s and Youth Hospital Auf der Bul, Hannover, Germany. Written informed consents were obtained from all the participating adults and guardians of affected individuals. Specific written informed consent was obtained for publishing the patients’ photographs. This study adhered to the World Medical Association Declaration of Helsinki (2013).

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The authors declare no competing interests.

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Polla, D.L., Farazi Fard, M.A., Tabatabaei, Z. et al. Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder. Genet Med (2021).

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