De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies

Konrad Platzer, Heinrich Sticht, Stacey L. Edwards, William Allen, Kaitlin M. Angione, Maria T. Bonati, Campbell Brasington, Megan T. Cho, Laurie A. Demmer, Tzipora Falik-Zaccai, Candace N. Gamble, Yorck Hellenbroich, Maria Iascone, Fernando Kok, Sonal Mahida, Hanna Mandel, Thorsten Marquardt, Kirsty McWalter, Bianca Panis, Alexander PeplerHailey Pinz, Luiza Ramos, Deepali N. Shinde, Constance Leonie Smith-Hicks, Alexander P.A. Stegmann, Petra Stöbe, Constance T.R.M. Stumpel, Carolyn Wilson, Johannes R. Lemke, Nataliya Di Donato, Kenneth G. Miller, Rami Jamra

Research output: Contribution to journalArticle

Abstract

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.

Original languageEnglish (US)
Pages (from-to)203-212
Number of pages10
JournalAmerican Journal of Human Genetics
Volume104
Issue number2
DOIs
StatePublished - Feb 7 2019

Fingerprint

Exome
Intellectual Disability
Clustered Regularly Interspaced Short Palindromic Repeats
Axonal Transport
Corpus Callosum
Caenorhabditis elegans
Brain
Locomotion
Lysosomes
Atrophy
Phenotype
Amino Acids
Neurodevelopmental Disorders
Cerebellar Hypoplasia
Polymicrogyria

Keywords

  • brain anomalies
  • de novo
  • developmental delay
  • intellectual disability
  • MAPK8IP3
  • neurodevelopmental disorder
  • polymicrogyria

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Platzer, K., Sticht, H., Edwards, S. L., Allen, W., Angione, K. M., Bonati, M. T., ... Jamra, R. (2019). De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies. American Journal of Human Genetics, 104(2), 203-212. https://doi.org/10.1016/j.ajhg.2018.12.008

De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies. / Platzer, Konrad; Sticht, Heinrich; Edwards, Stacey L.; Allen, William; Angione, Kaitlin M.; Bonati, Maria T.; Brasington, Campbell; Cho, Megan T.; Demmer, Laurie A.; Falik-Zaccai, Tzipora; Gamble, Candace N.; Hellenbroich, Yorck; Iascone, Maria; Kok, Fernando; Mahida, Sonal; Mandel, Hanna; Marquardt, Thorsten; McWalter, Kirsty; Panis, Bianca; Pepler, Alexander; Pinz, Hailey; Ramos, Luiza; Shinde, Deepali N.; Smith-Hicks, Constance Leonie; Stegmann, Alexander P.A.; Stöbe, Petra; Stumpel, Constance T.R.M.; Wilson, Carolyn; Lemke, Johannes R.; Di Donato, Nataliya; Miller, Kenneth G.; Jamra, Rami.

In: American Journal of Human Genetics, Vol. 104, No. 2, 07.02.2019, p. 203-212.

Research output: Contribution to journalArticle

Platzer, K, Sticht, H, Edwards, SL, Allen, W, Angione, KM, Bonati, MT, Brasington, C, Cho, MT, Demmer, LA, Falik-Zaccai, T, Gamble, CN, Hellenbroich, Y, Iascone, M, Kok, F, Mahida, S, Mandel, H, Marquardt, T, McWalter, K, Panis, B, Pepler, A, Pinz, H, Ramos, L, Shinde, DN, Smith-Hicks, CL, Stegmann, APA, Stöbe, P, Stumpel, CTRM, Wilson, C, Lemke, JR, Di Donato, N, Miller, KG & Jamra, R 2019, 'De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies', American Journal of Human Genetics, vol. 104, no. 2, pp. 203-212. https://doi.org/10.1016/j.ajhg.2018.12.008
Platzer, Konrad ; Sticht, Heinrich ; Edwards, Stacey L. ; Allen, William ; Angione, Kaitlin M. ; Bonati, Maria T. ; Brasington, Campbell ; Cho, Megan T. ; Demmer, Laurie A. ; Falik-Zaccai, Tzipora ; Gamble, Candace N. ; Hellenbroich, Yorck ; Iascone, Maria ; Kok, Fernando ; Mahida, Sonal ; Mandel, Hanna ; Marquardt, Thorsten ; McWalter, Kirsty ; Panis, Bianca ; Pepler, Alexander ; Pinz, Hailey ; Ramos, Luiza ; Shinde, Deepali N. ; Smith-Hicks, Constance Leonie ; Stegmann, Alexander P.A. ; Stöbe, Petra ; Stumpel, Constance T.R.M. ; Wilson, Carolyn ; Lemke, Johannes R. ; Di Donato, Nataliya ; Miller, Kenneth G. ; Jamra, Rami. / De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 2. pp. 203-212.
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AU - Angione, Kaitlin M.

AU - Bonati, Maria T.

AU - Brasington, Campbell

AU - Cho, Megan T.

AU - Demmer, Laurie A.

AU - Falik-Zaccai, Tzipora

AU - Gamble, Candace N.

AU - Hellenbroich, Yorck

AU - Iascone, Maria

AU - Kok, Fernando

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AU - Mandel, Hanna

AU - Marquardt, Thorsten

AU - McWalter, Kirsty

AU - Panis, Bianca

AU - Pepler, Alexander

AU - Pinz, Hailey

AU - Ramos, Luiza

AU - Shinde, Deepali N.

AU - Smith-Hicks, Constance Leonie

AU - Stegmann, Alexander P.A.

AU - Stöbe, Petra

AU - Stumpel, Constance T.R.M.

AU - Wilson, Carolyn

AU - Lemke, Johannes R.

AU - Di Donato, Nataliya

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