Abstract
BACKGROUND: Severe congenital neutropenia (SCN) is a heterogeneous hematopoietic disorder characterized by impaired granulocyte maturation and increased susceptibility to infections. Over 25 genes have been linked to SCN, yet the molecular pathogenesis remains unknown in 30%-50% of cases. This study aimed to expand the understanding of SEC61A1 variant-mediated diseases. METHODS: Clinical data were collected from the patient. Whole-exome sequencing was performed, followed by Sanger sequencing for familial validation. Bioinformatics, conservation, and protein structural analyses were conducted to evaluate candidate variants. RESULTS: We report an 11-year-old boy with decreased neutrophils and lymphocytes, and elevated proportions of monocytes and eosinophils. Bone marrow showed granulocytic hyperplasia with maturation arrest and nuclear abnormalities. Flow cytometric analysis of bone marrow cells is indicative of aberrant myeloid antigen differentiation and impaired granulocytic maturation. A novel de novo pathogenic SEC61A1 variant (c.1135 T > C; p.Trp379Arg) was identified. Structural analysis suggested that this variant may disrupt protein conformational stability. CONCLUSIONS: The SEC61A1 c.1135 T > C (p.Trp379Arg) variant is considered likely pathogenic. This is the second reported SEC61A1 variant associated with SCN11, expanding the genetic and phenotypic spectrum of SCN.