Adult onset neurodegenerative disorder

Gene: DNAJC7

As reviewed by Cassandra Smith, there are 3 affected siblings from a consanguineous family, harbouring a homozygous DNAJC7 c.518dupC p.(Ala174Cysfs*27) variant. Patients exhibited progressive muscle weakness, limb atrophy, bulbar palsy, and respiratory failure. Diagnosed with ALS with TDP-43 pathology. Variable age of disease onset between siblings: early 30s to 65yo (PMID:40802071 Yamashita et al., 2025).
Until more evidence emerges for biallelic inheritance, the MOI should remain monoallelic.
This gene is not yet associated with a disease in OMIM (accessed 15th Oct 2025).

Created: 15 Oct 2025, 12:21 p.m. | Last Modified: 15 Oct 2025, 12:21 p.m.

Panel Version: 8.7

Phenotypes
familial amyotrophic lateral sclerosis, MONDO:0005144

Publications

• 40802071

One report of biallelic inheritance

PMID:40802071 - three affected siblings with homozygous frameshift variant. Phenotype is ALS. Parents unaffected

Created: 9 Oct 2025, 8 p.m. | Last Modified: 9 Oct 2025, 8:01 p.m.

Panel Version: 8.3

Publications

• 40802071

Publications

• 31768050
• 35039179
• 34233860
• 32897108
• 37870677
• 35456894

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.

Created: 4 May 2024, 5:32 p.m. | Last Modified: 4 May 2024, 5:32 p.m.

Panel Version: 5.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen or Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022), because the ALS Gene Curation Expert Panel only scores protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.

Created: 9 Jan 2024, 5:59 p.m. | Last Modified: 9 Jan 2024, 6:13 p.m.

Panel Version: 4.45

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 9 Jan 2024, 5:28 p.m. | Last Modified: 9 Jan 2024, 5:28 p.m.

Panel Version: 4.45

I don't know

Two cohort studies in ALS patients identified 11 and 1 patient, respectively, with variants in DNAJC7. Seven of these are putative PTVs. No segregation or functional data. A small number of individuals with LOF variants are present in gnomad albeit less than expected. Given these are cohort studies, and an adult-onset condition, potentially of variable penetrance, we have taken a cautious approach and rated Amber for now but would be interested in other expert opinions. No PMID yet.
Sources: Literature

Created: 8 Sep 2020, 10:33 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
amyotrophic lateral sclerosis

Publications

• https://doi.org/10.1212/NXG.0000000000000503