2. Academic Validation
  3. Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder

  • Genet Med. 2021 Jul;23(7):1246-1254. doi: 10.1038/s41436-021-01133-w.
Daniel L Polla # 1 2,  Mohammad Ali Farazi Fard # 3,  Zahra Tabatabaei 3,  Parham Habibzadeh 3,  Olga A Levchenko 4,  Pooneh Nikuei 5,  Periklis Makrythanasis 6 7,  Mureed Hussain 1,  Sandra von Hardenberg 8,  Sirous Zeinali 9,  Mohammad-Sadegh Fallah 10,  Janneke H M Schuurs-Hoeijmakers 1,  Mohsin Shahzad 11 12 13,  Fareeha Fatima 14,  Neelam Fatima 14,  Laura Donker Kaat 15,  Hennie T Bruggenwirth 15,  Leah R Fleming 16,  John Condie 17,  Rafal Ploski 18,  Agnieszka Pollak 18,  Jacek Pilch 19,  Nina A Demina 4,  Alena L Chukhrova 4,  Vasilina S Sergeeva 4,  Hanka Venselaar 20,  Amira T Masri 21,  Hanan Hamamy 6,  Federico A Santoni 6 22,  Katrin Linda 1,  Zubair M Ahmed 11,  Nael Nadif Kasri 1,  Arjan P M de Brouwer 1,  Anke K Bergmann 8,  Sven Hethey 23,  Majid Yavarian 3,  Muhammad Ansar 6 24,  Saima Riazuddin 11,  Sheikh Riazuddin 12 13,  Mohammad Silawi 3,  Gaia Ruggeri 25,  Filomena Pirozzi 25,  Ebrahim Eftekhar 5,  Afsaneh Taghipour Sheshdeh 3,  Shima Bahramjahan 3,  Ghayda M Mirzaa 25 26 27,  Alexander V Lavrov 4,  Stylianos E Antonarakis 6 28,  Mohammad Ali Faghihi 3 29,  Hans van Bokhoven 30
Affiliations

Affiliations

  • 1 Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 2 CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
  • 3 Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Fars, Iran.
  • 4 Research Centre for Medical Genetics, Moscow, Russia.
  • 5 Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
  • 6 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • 7 Biomedical Research Foundation Academy of Athens, Athens, Greece.
  • 8 Department of Human Genetics, Hannover Medical School, Hanover, Germany.
  • 9 Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
  • 10 Department of Medical Genetics, Kawsar Human Genetics Research Center, Tehran, Iran.
  • 11 Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
  • 12 Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
  • 13 Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical Research Center, University of Health Sciences, Lahore, Pakistan.
  • 14 Center for Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan.
  • 15 Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 16 St. Luke's Children's Genetics and Metabolic Clinic, Boise, ID, USA.
  • 17 St Luke's Pediatric Neurology Clinic, Boise, ID, USA.
  • 18 Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland.
  • 19 Department of Pediatric Neurology, Medical University of Silesia, Katowice, Poland.
  • 20 Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 21 Faculty of Medicine, Pediatric Department Division of Child Neurology, The University of Jordan, Amman, Jordan.
  • 22 Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne, Switzerland.
  • 23 Department of Neuropediatrics, Children's and Youth Hospital Auf der Bult, Hanover, Germany.
  • 24 Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
  • 25 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
  • 26 Department of Pediatrics, University of Washington, Seattle, WA, USA.
  • 27 Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
  • 28 Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
  • 29 Department of Psychiatry & Behavioral Sciences, Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
  • 30 Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. [email protected].
  • # Contributed equally.
PMID: 33824500 DOI: 10.1038/s41436-021-01133-w
Abstract

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.

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