Identification of two novel DNAJC12 gene variants in a patient with mild hyperphenylalaninemia.

Background: Recently, variants in DNAJC12 were reported to be a novel genetic cause of hyperphenylalaninemia (HPA); however, thus far, fewer than fifty cases have been reported worldwide. Some patients with DNAJC12 deficiency present with mild HPA, developmental delay, dystonia, Parkinson's disease and psychiatric abnormalities.

Methods: Herein, we report the case of a two-month-old Chinese infant with mild HPA, detected by newborn screening. Genetic etiology of the HPA patient was analyzed by Next-generation sequencing (NGS) and Sanger sequencing. Functional consequences of this variant were investigated using an in vitro minigene splicing assay.

Results: Two novel compound heterozygous variants in DNAJC12, c.158-1G > A and c.336delG, were detected in our patient with asymptomatic HPA. The c.158-1G > A canonical splice-site variant demonstrated mis-splicing on an in vitro minigene assay and was predicted to lead to introduction of a premature termination codon p.(Val53AspfsTer15). In silico prediction tools designated c.336delG as a truncating variant leading to a frameshift p.(Met112IlefsTer44). Both variants segregated with unaffected parents and were annotated as "likely pathogenic".

Conclusions: In this study, we report an infant with mild HPA and compound heterozygous variants in DNAJC12. For patients with HPA, DNAJC12 deficiency should be considered when phenylalanine hydroxylase and tetrahydrobiopterin metabolic defects are excluded.