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SMARCD2 is implicated in autosomal recessive Specific Granule Deficiency, a rare neutrophil granule biogenesis disorder characterized by severe neutropenia and life-threatening infections. Clinical presentation includes delayed cord separation, refractory neutropenia, and recurrent bacterial infections.
Two unrelated probands have been reported with biallelic loss-of-function variants in SMARCD2. The first case was a homozygous c.511C>T (p.Gln171Ter) variant in a male infant with type 2 SGD successfully treated by hematopoietic stem cell transplantation (PMID:35320004). A second patient harbored a homozygous splice-site mutation, confirmed by exome sequencing, providing independent genetic evidence (PMID:33279574). No segregation beyond the index cases has been reported.
Both reported variants are predicted to abolish SMARCD2 function, consistent with an autosomal recessive inheritance. Variant spectrum is limited to truncating and splice-site mutations to date. No recurrent or founder alleles have been identified.
Functional assays in patient-derived neutrophils demonstrated immature morphology lacking multilobed nuclei, absence of specific granule proteins such as lactoferrin with preserved myeloperoxidase, severely impaired chemotaxis, and defective in vitro killing of Staphylococcus aureus, confirming a pathogenic role for SMARCD2 deficiency (PMID:33279574). Hematopoietic stem cell transplantation restored normal granulopoiesis and clinical remission.
No conflicting evidence has been published. Together, genetic and functional data support a moderate clinical validity for SMARCD2 in Specific Granule Deficiency. Genetic testing for SMARCD2 and early consideration of HSCT are crucial for diagnosis and management.
Key Take-home: SMARCD2 biallelic loss-of-function variants cause autosomal recessive Specific Granule Deficiency, with definitive functional deficits in neutrophil granule formation and a curative response to stem cell transplantation.
Gene–Disease AssociationModerate2 probands with biallelic loss-of-function variants and consistent functional validation Genetic EvidenceLimitedTwo unrelated homozygous LoF variants in SMARCD2; autosomal recessive inheritance; no segregation data Functional EvidenceModeratePatient neutrophils show defective granule formation, chemotaxis, and bactericidal activity with rescue by HSCT |