DNAJC21 – Shwachman-Diamond syndrome

Shwachman-Diamond syndrome (SDS) is an autosomal recessive bone marrow failure disorder characterized by cytopenia, exocrine pancreatic insufficiency, skeletal abnormalities, and multisystem involvement. A 5-year-old girl with cytopenia, dysmorphic features, short stature, global developmental delay, myopia, and recurrent infections underwent reanalysis of exome data that identified a homozygous splice-site variant c.983+1G>A in DNAJC21. RNA sequencing demonstrated exon 7 skipping with an 88-nucleotide deletion, confirming loss of normal transcript ([PMID:38408162]).

In a cohort of 405 marrow failure cases, targeted sequencing revealed a second patient harboring a homozygous DNAJC21 splice-region deletion c.98-2delA presenting with failure to thrive and chronic diarrhea, expanding the mutation spectrum in SDS ([PMID:40209608]).

Multi-patient studies estimate DNAJC21 biallelic variants account for a minority of SDS-like cases among mutation-positive individuals, supporting allelic heterogeneity alongside SBDS, EFL1, and SRP54 ([PMID:37226705]). A systematic review of 156 SDS patients underscored the autosomal recessive inheritance and core features—96.8% cytopenia; 83.3% pancreatic dysfunction; 83.3% failure to thrive—though the proportion attributable to DNAJC21 was not specified ([PMID:37803383]).

Genetic evidence comprises two unrelated probands with biallelic splicing defects, consistent AR transmission; no extended segregation data have been reported. The recurrent splice-site variants lead to loss of function, aligning with a ribosome biogenesis defect common to SDS genes.

Functional modeling in zebrafish demonstrated that dnajc21 loss recapitulates SDS hallmarks—cytopenia, impaired hematopoietic differentiation, growth retardation, and defective protein synthesis—and reveals disrupted nucleotide metabolism. Notably, exogenous nucleoside supplementation rescued neutrophil counts, elucidating a novel mechanism of pathogenicity ([PMID:39138265]).

Integration of clinical, genetic, and functional data supports a Moderate level of clinical validity. While genetic evidence is Limited (two probands), functional studies provide Moderate support for loss-of-function mechanism. DNAJC21 sequencing should be incorporated in diagnostic panels for suspected SDS to enable accurate counseling and management.

Key Take-home: Biallelic splice-site variants in DNAJC21 cause autosomal recessive SDS; functional validation in zebrafish underpins diagnostic and therapeutic strategies.

References

• Journal of pediatric hematology/oncology • 2024 • A Rare Inherited Bone Marrow Failure Syndrome Disclosed by Reanalysis of the Exome Data of a Patient Evaluated for Cytopenia and Dysmorphic Features. PMID:38408162
• Blood cells, molecules & diseases • 2025 • Clinical and genetic spectrum of SBDS and DNAJC21 gene variants in bone marrow failure cases: Atypical and cryptic presentations. PMID:40209608
• Haematologica • 2023 • Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants. PMID:37226705
• BMC pediatrics • 2023 • Clinical features, epidemiology, and treatment of Shwachman-Diamond syndrome: a systematic review. PMID:37803383
• Leukemia • 2024 • Loss of Dnajc21 leads to cytopenia and altered nucleotide metabolism in zebrafish. PMID:39138265

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