DNAJC12-associated developmental delay, movement disorder, and mild hyperphenylalaninemia identified by whole-exome
Danielle Veenma1, Dawn Cordeiro1, Neal Sondheimer1,2,3
1Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.
Insights
Two new patients with DNAJC12 gene variants show mild hyperphenylalaninemia and global developmental delay. Early DNAJC12 genetic testing is crucial for diagnosing this inherited neurotransmitter disorder.
Area of Science:
- Genetics
- Neuroscience
- Biochemistry
Background:
- DNAJC12-associated disorder is a rare inherited condition affecting neurotransmitter pathways.
- It is characterized by hyperphenylalaninemia, movement disorders, and intellectual disability.
- Recent reports highlight its significance as a distinct genetic diagnosis.
Observation:
- Two siblings presented with global developmental delay (GDD) and mild hyperphenylalaninemia.
- Cerebrospinal fluid analysis revealed low levels of homovanillic acid and 5-hydroxyindoleacetic acid.
- Initial whole-exome sequencing was normal, but re-analysis after disease description identified a homozygous DNAJC12 variant.
Findings:
- Confirmed diagnosis of DNAJC12-associated hyperphenylalaninemia, movement disorder, and intellectual disability in both patients.
- Identified a homozygous c.58_59delGG (p.(Gly20Metfs*2)) variant in the DNAJC12 gene.
- Demonstrated that mild hyperphenylalaninemia and GDD can be indicators of this disorder.
Implications:
- Highlights the importance of targeted DNAJC12 genetic testing for early diagnosis.
- Suggests re-evaluation of previous normal genetic testing in patients with suggestive phenotypes.
- Emphasizes the need for increased awareness among clinicians regarding this newly described genetic disorder.
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.
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