Submission Details

DNAJC21 was first reported in relation to autosomal recessive DNAJC21-related bone marrow failure syndrome in 2016 (Tummala et al., PMID: 27346687). Clinical manifestations are highly variable, and include pancytopenia, bone marrow failure, growth restriction, recurrent infections, dysmorphic features, skeletal anomalies, pancreatic dysfunction, liver dysfunction, dental anomalies, eczema, sparse hair, genitourinary anomalies, retinal dystrophy, short telomeres, growth hormone deficiency, and acute myeloid leukemia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern or phenotypic variability between bone marrow failure syndrome 3 (MIM: 617052) and Shwachman-Diamond syndrome (NBK1756). Therefore, those disease entities have been lumped into a single disease entity, DNAJC21-related bone marrow failure syndrome. Ten variants (nonsense, frameshift, canonical splice site, and missense) that have been reported in 8 probands in 4 publications (PMIDs: 27346687, 28062395, 29146883, 35464845) are included in this curation. More evidence is available in the literature (PMIDs: 29700810, 35298850, 37186482, 35776903, 38408162) but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be biallelic loss of function. This gene-disease relationship is also supported by experimental evidence including biochemical function and functional alteration in patient cells (PMIDs: 37226705, 27346687). In summary, there is definitive evidence supporting the relationship between DNAJC21 and autosomal recessive DNAJC21-related bone marrow failure syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date March 11, 2025 (SOP Version 11).