Abstract
Hyperphenylalaninemia, movement disorder, and intellectual disability due to variants in DNAJC12 is a recently reported inherited neurotransmitter disorder. We report two new patients with this new genetic disorder. Patient 1 is a 6-year-11-month-old boy with mild hyperphenylalaninemia and global developmental delay (GDD). Seventeen-year-old male sibling of patient 1 had GDD from the first year of life. He had mild hyperphenylalaninemia at 11.5 years of age following his younger brother’s diagnosis. He had low levels of homovanillic acid and 5-hydroxyindolacetic acid in the cerebrospinal fluid. Whole-exome sequencing (WES) was normal in 2016. After the first description of DNAJC12-associated hyperphenylalaninemia, dystonia, and intellectual disability in 2017, WES re-analysis identified a homozygous c.58_59delGG (p.(Gly20Metfs*2)) variant in DNAJC12. His younger brother was homozygous for the same variant, confirming the diagnosis of DNAJC12-associated hyperphenylalaninemia, movement disorder, and intellectual disability. Mild hyperphenylalaninemia and GDD should warrant targeted DNAJC12 genetic testing for the early diagnosis of DNAJC12-associated hyperphenylalaninemia, movement disorder, and intellectual disability.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Anikster Y, Haack TB, Vilboux T, Pode-Shakked B, Thöny B, Shen N, et al. Biallelic mutations in DNAJC12 cause hyperphenylalaninemia, dystonia, and intellectual disability. Am J Hum Genet. 2017;100:257–66.
Straniero L, Guella I, Cilia R, Parkkinen L, Rimoldi V, Young A, et al. DNAJC12 and dopa-responsive nonprogressive parkinsonism. Ann Neurol. 2017;82:640–6.
van Spronsen FJ, Himmelreich N, Rüfenacht V, Shen N, Vliet DV, Al-Owain M, et al. Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability. J Med Genet. 2017. https://doi.org/10.1136/jmedgenet-2017-104875.
de Sain-van der Velden MGM, Kuper WFE, Kuijper MA, van Kats LAT, Prinsen HCMT, Balemans ACJ, et al. Beneficial effect of BH4 treatment in a 15-year-old boy with biallelic mutations in DNAJC12. JIMD Rep. 2018. https://doi.org/10.1007/8904_2017_86.
Huttlin EL, Ting L, Bruckner RJ, Gebreab F, Gygi MP, Szpyt J, et al. The BioPlex Network: a systematic exploration of the human interactome. Cell. 2015;162:425–40.
Dekker SL, Kampinga HH, Bergink S. DNAJs: more than substrate delivery to HSPA. Front Mol Biosci. 2015;2:35.
Blau N, Martinez A, Hoffmann GF, Thöny B. DNAJC12 deficiency: a new strategy in the diagnosis of hyperphenylalaninemias. Mol Genet Metab. 2018;123:1–5.
Choi J, Djebbar S, Fournier A, Labrie C. The co-chaperone DNAJC12 binds to Hsc70 and is upregulated by endoplasmic reticulum stress. Cell Stress Chaperon. 2014;19:439–46.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
Acknowledgements
We thank the parents for allowing us to present their children’s results.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Veenma, D., Cordeiro, D., Sondheimer, N. et al. DNAJC12-associated developmental delay, movement disorder, and mild hyperphenylalaninemia identified by whole-exome sequencing re-analysis. Eur J Hum Genet 26, 1867–1870 (2018). https://doi.org/10.1038/s41431-018-0237-9
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41431-018-0237-9
This article is cited by
-
Impaired cognitive function and decreased monoamine neurotransmitters in the DNAJC12 gene knockout mouse model
Orphanet Journal of Rare Diseases (2025)
-
Central biogenic amine deficiency with concomitant exploratory behavioral deficits in Dnajc12 knock-out mice
npj Parkinson's Disease (2025)
-
Hyperphenylalaninemia and serotonin deficiency in Dnajc12-deficient mice
Communications Biology (2024)
-
Restless legs syndrome in DNAJC12 deficiency
Neurological Sciences (2023)
-
DNACJ12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant
Metabolic Brain Disease (2021)
