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 Ploski; Agnieszka 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

doi:10.1038/s41436-021-01133-w

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

Clinical Genetics

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	1246-1254
Number of pages	9
Journal	Genetics in Medicine
Volume	23
Issue number	7
DOIs	https://doi.org/10.1038/s41436-021-01133-w
Publication status	Published - 6 Apr 2021

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nihms-1761699Accepted author manuscript, 1.37 MBLicence: CC BY-NC-ND

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Polla, D. L., Farazi Fard, M. A., Tabatabaei, Z., Habibzadeh, P., Levchenko, O. A., Nikuei, P., Makrythanasis, P., Hussain, M., von Hardenberg, S., Zeinali, S., Fallah, M. S., Schuurs-Hoeijmakers, J. H. M., Shahzad, M., Fatima, F., Fatima, N., Kaat, L. D., Bruggenwirth, H. T., Fleming, L. R., Condie, J., ... van Bokhoven, H. (2021). Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder. Genetics in Medicine, 23(7), 1246-1254. https://doi.org/10.1038/s41436-021-01133-w

@article{01ef9fa83fe346f4892f0fdf1d5a6b76,

title = "Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.",

year = "2021",

month = apr,

day = "6",

doi = "10.1038/s41436-021-01133-w",

language = "English",

volume = "23",

pages = "1246--1254",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams & Wilkins",

number = "7",

}

Polla, DL, Farazi Fard, MA, Tabatabaei, Z, Habibzadeh, P, Levchenko, OA, Nikuei, P, Makrythanasis, P, Hussain, M, von Hardenberg, S, Zeinali, S, Fallah, MS, Schuurs-Hoeijmakers, JHM, Shahzad, M, Fatima, F, Fatima, N, Kaat, LD , Bruggenwirth, HT, Fleming, LR, Condie, J, Ploski, R, Pollak, A, Pilch, J, Demina, NA, Chukhrova, AL, Sergeeva, VS, Venselaar, H, Masri, AT, Hamamy, H, Santoni, FA, Linda, K, Ahmed, ZM, Nadif Kasri, N, de Brouwer, APM, Bergmann, AK, Hethey, S, Yavarian, M, Ansar, M, Riazuddin, S, Riazuddin, S, Silawi, M, Ruggeri, G, Pirozzi, F, Eftekhar, E, Taghipour Sheshdeh, A, Bahramjahan, S, Mirzaa, GM, Lavrov, AV, Antonarakis, SE, Faghihi, MA & van Bokhoven, H 2021, 'Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder', Genetics in Medicine, vol. 23, no. 7, pp. 1246-1254. https://doi.org/10.1038/s41436-021-01133-w

TY - JOUR

T1 - Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder

AU - Polla, Daniel L.

AU - Farazi Fard, Mohammad Ali

AU - Tabatabaei, Zahra

AU - Habibzadeh, Parham

AU - Levchenko, Olga A.

AU - Nikuei, Pooneh

AU - Makrythanasis, Periklis

AU - Hussain, Mureed

AU - von Hardenberg, Sandra

AU - Zeinali, Sirous

AU - Fallah, Mohammad Sadegh

AU - Schuurs-Hoeijmakers, Janneke H.M.

AU - Shahzad, Mohsin

AU - Fatima, Fareeha

AU - Fatima, Neelam

AU - Kaat, Laura Donker

AU - Bruggenwirth, Hennie T.

AU - Fleming, Leah R.

AU - Condie, John

AU - Ploski, Rafal

AU - Pollak, Agnieszka

AU - Pilch, Jacek

AU - Demina, Nina A.

AU - Chukhrova, Alena L.

AU - Sergeeva, Vasilina S.

AU - Venselaar, Hanka

AU - Masri, Amira T.

AU - Hamamy, Hanan

AU - Santoni, Federico A.

AU - Linda, Katrin

AU - Ahmed, Zubair M.

AU - Nadif Kasri, Nael

AU - de Brouwer, Arjan P.M.

AU - Bergmann, Anke K.

AU - Hethey, Sven

AU - Yavarian, Majid

AU - Ansar, Muhammad

AU - Riazuddin, Saima

AU - Riazuddin, Sheikh

AU - Silawi, Mohammad

AU - Ruggeri, Gaia

AU - Pirozzi, Filomena

AU - Eftekhar, Ebrahim

AU - Taghipour Sheshdeh, Afsaneh

AU - Bahramjahan, Shima

AU - Mirzaa, Ghayda M.

AU - Lavrov, Alexander V.

AU - Antonarakis, Stylianos E.

AU - Faghihi, Mohammad Ali

AU - van Bokhoven, Hans

PY - 2021/4/6

Y1 - 2021/4/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85103612834&partnerID=8YFLogxK

U2 - 10.1038/s41436-021-01133-w

DO - 10.1038/s41436-021-01133-w

M3 - Article

C2 - 33824500

AN - SCOPUS:85103612834

VL - 23

SP - 1246

EP - 1254

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 7

ER -

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder

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