Identification of an inherited pathogenic DNAJC12 variant in a patient with hyperphenylalalinemia

Hyperphenylalaninemia (HPA), an abnormal condition of phenylalanine metabolism, was recently reported to be caused by DNAJC12 mutations. As the heat shock co-chaperone, DNAJC12 prevents the aggregation of misfolded or aggregation-prone proteins and maintain the correct assembly and degradation. Here, we report a patient with unexplained HPA detected by newborn screening. Differential diagnoses of pterin profile and targeted next generation sequencing of excluded the most common causes of the defects of the enzyme phenylalanine hydroxylase or its cofactor tetrahydrobiopterin (BH4). Sanger sequencing revealed a novel homozygous deletion variant of c.262del in DNAJC12, which was predicted to produce the truncated protein (p.Q88SfsTer6) and was considered pathogenic to result in the symptoms of global developmental delays clinically. Treatment with the combination of BH4, the neurotransmitter precursors of dopamine and serotonin, and phenylalanine-restricted diet enabled the patient to improve his development and stabilize his phenylalanine level in a reasonable range. These findings expanded the spectrum of the DNAJC12 mutations and provided new insights on patient management, further supporting the causal relationships of DNAJC12 and HPA.