For Medical Professionals

Key Research

  • Start here: [2024 Publication of the KPTN chapter in GeneReviews] This page provides the most complete clinical description of KPTN syndrome to date, including prevalence, symptoms, treatment, and other information. https://www.ncbi.nlm.nih.gov/books/NBK605495/.

  • [2023 Publication in Oxford’s journal Brain:] Models of KPTN-related disorder implicate mTOR signaling in cognitive and overgrowth phenotypes, Maria O Levitin, Lettie E Rawlins, Gabriela Sanchez-Andrade, Osama A Arshad, Stephan C Collins, Stephen J Sawiak, Phillip H Iffland, Malin H L Andersson, Caleb Bupp, Emma L Cambridge, Eve L Coomber, Ian Ellis, Johanna C Herkert, Holly Ironfield, Logan Jory, Perrine F Kretz, Sarina G Kant, Alexandra Neaverson, Esther Nibbeling, Christine Rowley, Emily Relton, Mark Sanderson, Ethan M Scott, Helen Stewart, Andrew Y Shuen, John Schreiber, Liz Tuck, James Tonks, Thorkild Terkelsen, Conny van Ravenswaaij-Arts, Pradeep Vasudevan, Olivia Wenger, Michael Wright, Andrew Day, Adam Hunter, Minal Patel, Christopher J Lelliott, Peter B Crino, Binnaz Yalcin, Andrew H Crosby, Emma L Baple, Darren W Logan, Matthew E Hurles, Sebastian S Gerety,  Brain, 2023;, awad231, https://doi.org/10.1093/brain/awad231
  • [Pre-print version of the paper from July 2022]: Mouse and cellular models of KPTN-related disorder implicate mTOR signaling in cognitive and progressive overgrowth phenotypes. Maria O. Levitin, Lettie E Rawlins, Gabriela Sanchez-Andrade, Osama A. Arshad, Stephan C. Collins, Stephen J. Sawiak, Phillip H. Iffland II, Malin H.L. Andersson, Caleb Bupp, Emma L. Cambridge, Eve L. Coomber, Ian Ellis, Johanna C. Herkert, Holly Ironfield, Logan Jory, Perrine F. Kretz, Sarina G. Kant, Alexandra Neaverson, Esther Nibbeling, Christine Rowley, Emily Relton, Mark Sanderson, Ethan M. Scott, Helen Stewart, Andrew Y. Shuen, John Schreiber, Liz Tuck, James Tonks, Thorkild Terkelsen, Conny van Ravenswaaij-Arts, Pradeep Vasudevan, Olivia Wenger, Michael Wright, Andrew Day, Adam Hunter, Minal Patel, Christopher J. Lelliott, Peter B. Crino, Binnaz Yalcin, Andrew Crosby, Emma L. Baple, Darren W. Logan, Matthew E. Hurles, Sebastian S. Gerety. doi: https://doi.org/10.1101/2022.07.15.500213 https://www.biorxiv.org/content/10.1101/2022.07.15.500213v1

Published Research (oldest to newest): 

  • [The original 2013 article: Ohio USA] Baple EL, Maroofian R, Chioza BA, Izadi M, Cross HE, Al-Turki S, Barwick K, Skrzypiec A, Pawlak R, Wagner K, Coblentz R, Zainy T, Patton MA, Mansour S, Rich P, Qualmann B, Hurles ME, Kessels MM, Crosby AH. Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures. Am J Hum Genet. 2014 Jan 2;94(1):87-94. doi: 10.1016/j.ajhg.2013.10.001. Epub 2013 Nov 14. PMID: 24239382; PMCID: PMC3882725. https://doi.org/10.1016/j.ajhg.2013.10.001 
  • [Estonia] Pajusalu S, Reimand T, Õunap K. Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome. Am J Med Genet A. 2015 Aug;167A(8):1913-5. doi: 10.1002/ajmg.a.37105. Epub 2015 Apr 5. PMID: 25847626. https://doi.org/10.1002/ajmg.a.37105 
  • [Kansas City USA] Thiffault I, Atherton A, Heese BA, T Abdelmoity A, Pawar K, Farrow E, Zellmer L, Miller N, Soden S, Saunders C. Pathogenic variants in KPTN gene identified by clinical whole-genome sequencing. Cold Spring Harb Mol Case Stud. 2020 Jun 12;6(3):a003970. doi: 10.1101/mcs.a003970. PMID: 32358097; PMCID: PMC7304362. https://doi.org/10.1101/mcs.a003970 
  • [Brazil] Lucena PH, Armani-Franceschi G, Bispo-Torres AC, Bandeira ID, Lucena MFG, Maldonado I, Veiga MF, Miguel D, Lucena R. KPTN gene homozygous variant-related syndrome in the northeast of Brazil: A case report. Am J Med Genet A. 2020 Apr;182(4):762-767. doi: 10.1002/ajmg.a.61492. Epub 2020 Jan 30. PMID: 31999056.https://doi.org/10.1002/ajmg.a.61492 
  • [Spain] Pacio Miguez, M., Santos‐Simarro, F., García‐Miñaúr, S., Velázquez Fragua, R., Del Pozo, Á., Solís, M., Jiménez Rodríguez, C., Rufo‐Rabadán, V., Fernandez, V.E., Rueda, I. and Gomez del Pozo, M.V., 2020. Pathogenic variants in KPTN, a rare cause of macrocephaly and intellectual disability. American Journal of Medical Genetics Part A, 182(10), pp.2222-2225. https://doi.org/10.1002/ajmg.a.61778
  • [Germany] Horn S, Danyel M, Erdmann N, Boschann F, Gunnarsson C, Biskup S, Juengling J, Potratz C, Prager C, Kaindl AM. Case report: KPTN gene-related syndrome associated with a spectrum of neurodevelopmental anomalies including severe epilepsy. Front Neurol. 2023 Jan. https://doi.org/10.3389/fneur.2022.1113811
  • [Pakistan] Liaqat K, Bharadwaj T, Shah K, et al., Nonsense variant in a consanguineous family expands the phenotype of KPTN gene-related syndrome to include hearing impairment. Clinical Genetics. 2023;104(4):499‐501. doi:10.1111/cge.14390

Research: Overview of the mTOR pathway 

(See page 189 for a diagram including KICSTOR, and pages 195-196 for more information on mTOR in the brain and in neurodevelopmental disorders)

The role of KICSTOR (which includes KPTN) in the mTOR process

  • Wolfson, R. L., Chantranupong, L., Wyant, G. A., Gu, X., Orozco, J. M., Shen, K., Condon, K. J., Petri, S., Kedir, J., Scaria, S. M., Abu-Remaileh, M., Frankel, W. N., & Sabatini, D. M. (2017). KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature, 543(7645), 438–442. https://doi.org/10.1038/nature21423

Information about KICS2, another protein in the KICSTOR complex. Mutations present similarly to KPTN

  • Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy. Buchert, Rebecca et al. The American Journal of Human Genetics, Volume 112, Issue 2, 374 – 393. [February 2024] https://doi.org/10.1016/j.ajhg.2024.12.019

KPTN Overview:

Unique Variants of KPTN:

Windows of Hope Project – (see “MASD Syndrome” on the alphabetical list)