Hyperphenylalaninemia via the DNAJC12 Gene

Phenylketonuria (PKU) and deficiencies of tetrahydrobiopterin (BH4) metabolism are inborn errors of metabolism that are associated with hyperphenylalaninemia (HPA) (Blau et al. 2014; Regier and Greene 2017). Deficiencies of BH4 metabolism are also associated with deficiencies in the neurotransmitters dopamine and serotonin (Blau et al. 2014). Recently, six individuals with clinical and biochemical features suggestive of either PKU or a BH4 metabolic defect were reported from four unrelated, consanguineous families. However, none of these individuals harbored pathogenic variants in genes previously known to be associated with these disorders. Whole exome sequencing (WES) revealed homozygous sequence variants in the DNAJC12 gene in all six individuals (Anikster et al. 2017).

Five of the six individuals were symptomatic before a diagnosis was made. All of the symptomatic patients exhibited a movement disorder that was similar to that observed in individuals with BH4 metabolic deficiencies, and was the reason they were brought to clinical attention. These patients exhibited HPA, though their urinary pterin measurements and DHPR activity from dried blood spots showed no evidence of a BH4 metabolic defect. However, analysis of the cerebrospinal fluid (CSF) revealed deficiencies of dopamine and serotonin, as well as an elevated homovanillic acid/5-hydroxyindoleacetic acid (HVA/HIAA) ratio (Anikster et al. 2017).

All patients were treated with BH4, with or without L-Dopa/carbidopa/5-hydroxytryptophan. Patients were reported to show a favorable response to treatment, particularly if treatment was started early. The authors suggest that all individuals with HPA, no causative variants in the PAH gene, and negative screening results for a BH4 metabolic defect should have genetic analysis of the DNAJC12 gene performed (Anikster et al. 2017).

Current knowledge about DNAJC12-associated hyperphenylalaninemia deficiency suggests that this is an autosomal recessive disorder (Anikster et al. 2017). To date, one gross deletion, one missense variant, and one splice variant have been reported.

The DNAJC12 gene encodes a heat shock co-chaperone family member protein, which has been shown to interact with the phenylalanine, tyrosine and tryptophan hydroxylases.

Clinical sensitivity is difficult to estimate because only a small number of patients have been reported. Based on the currently reported patients, analytical sensitivity may be ~50%, as half of the families reported in the literature were found to have gross deletions that may not be detectable via direct sequencing (Anikster et al. 2017).

This test provides full coverage of all coding exons of the DNAJC12 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).