Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder

Daniel L. Polla, Mohammad Ali Farazi Fard, Zahra Tabatabaei, Parham Habibzadeh, Olga A. Levchenko, Pooneh Nikuei, Periklis Makrythanasis, Mureed Hussain, Sandra von Hardenberg, Sirous Zeinali, Mohammad Sadegh Fallah, Janneke H.M. Schuurs-Hoeijmakers, Mohsin Shahzad, Fareeha Fatima, Neelam Fatima, Laura Donker Kaat, Hennie T. Bruggenwirth, Leah R. Fleming, John Condie, Rafal PloskiAgnieszka Pollak, Jacek Pilch, Nina A. Demina, Alena L. Chukhrova, Vasilina S. Sergeeva, Hanka Venselaar, Amira T. Masri, Hanan Hamamy, Federico A. Santoni, Katrin Linda, Zubair M. Ahmed, Nael Nadif Kasri, Arjan P.M. de Brouwer, Anke K. Bergmann, Sven Hethey, Majid Yavarian, Muhammad Ansar, Saima Riazuddin, Sheikh Riazuddin, Mohammad Silawi, Gaia Ruggeri, Filomena Pirozzi, Ebrahim Eftekhar, Afsaneh Taghipour Sheshdeh, Shima Bahramjahan, Ghayda M. Mirzaa, Alexander V. Lavrov, Stylianos E. Antonarakis, Mohammad Ali Faghihi, Hans van Bokhoven*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)
51 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)1246-1254
Number of pages9
JournalGenetics in Medicine
Issue number7
Publication statusPublished - 6 Apr 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.


Dive into the research topics of 'Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder'. Together they form a unique fingerprint.

Cite this