Submission Details

General Description: The DNAJC19 gene was first reported in relation to 3-methylglutaconic aciduria in the Canadian Dariusleut Hutterite community in 2006 (Davey et al., PMID: 16055927). Several other affected individuals from a diverse range of ethnicities have since been identified, frequently presenting before the age of 3 years with dilated or noncompaction cardiomyopathy, often with a prolonged QT interval. Other phenotypes associated with this syndromic disorder include cerebellar ataxia, mild muscle weakness, growth failure, microcytic anemia, mild non-progressive mental retardation, male genital abnormalities, and 3-methylglutaconic aciduria. At the cellular level, patients exhibit reduced activity of multiple mitochondrial complexes (PMID: 22797137, PMID: 27426421). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism and mode of inheritance (autosomal recessive) to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited DNAJC19 variants have been lumped into a single disease entity, referred to as 3-methylglutaconic aciduria type V (MONDO:0012435, MIM #610198).

Summary of Case Level Data: 10.2 POINTS Four suspected pathogenic variants were scored as part of this curation (one nonsense, one frameshift, and two affecting splicing), which have been collectively reported in fourteen probands in four publications (PMID: 16055927, PMID: 22797137, PMID: 27928778, PMID: 27426421). All fourteen probands were homozygous for their respective variants, and thirteen were reported to have consanguineous parents (PMID: 16055927, PMID: 27928778, PMID: 27426421). Limited segregation evidence was available in one of these publications (PMID: 16055927), but did not contribute to the scoring of the gene-disease relationship.

Summary of Case-Control Data: 0 POINTS This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level.

Mechanism for Disease: The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by the absence of a gene product (PMID: 22797137). All probands found for this curation harbored two variant alleles within the DNAJC19 locus.

Experimental Evidence: 3 POINTS This gene-disease association is also supported by experimental evidence that DNAJC19 is an ortholog of yeast Tim14, which localizes to the inner mitochondrial membrane and functions as a key component of the TIM23 translocase complex responsible for importing nuclear-encoded proteins into the mitochondria (PMID: 14517234). A yeast model of Tim14 depletion has identified this DNAJC19 ortholog as required for nuclear protein import into mitochondria and for yeast cell growth, matching both the decreased activity of mitochondrial complexes and the growth failure shown by the human patients (PMID: 14517234). The results of mitochondria-oriented mass spectrometry and proteinase K cleavage experiments in human cells are similarly consistent with DNAJC19 localization to the inner mitochondrial membrane and interaction with the prohibitin complex, which performs a scaffolding function at that site (PMID: 24856930). DNAJC19 has been further linked to mitochondria in cardiac muscle specifically by the finding that patient-derived induced pluripotent stem cells that have been differentiated into beating cardiomyocytes exhibit fragmented mitochondrial networks, abnormally shaped mitochondria with disorganized cristae, and imbalanced splicing of the mitochondrial fusion regulator OPA1 to favor mitochondrial fission (PMID: 32046906). Finally, DNAJC19 loss-of-function has been confirmed as the mechanism of pathogenicity by the finding that DNAJC19 depletion from non-patient HEK293T cells triggers decreased cell growth, abnormal mitochondrial morphology, defects in OPA1 splicing, and abnormal acylation of cardiolipin, an acidic lipoprotein present in the inner mitochondrial membrane that is critical for enzymatic activity in the respiratory chain (PMID: 32046906).

Summary Statement: In summary, DNAJC19 is strongly associated with 3-methylglutaconic aciduria type V. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification.