Clinical characterization and structural modeling of a novel de novo SPTBN1 missense variant in a Chinese child

Abstract Background SPTBN1 encodes βII-spectrin, a cytoskeletal protein essential for neuronal structure and function. Pathogenic variants in this gene cause a neurodevelopmental disorder known as DDISBA (Developmental Delay, Impaired Speech, and Behavioral Abnormalities). To date, reports of SPTBN1-related disorders in the Chinese population are notably limited. Methods Trio-based whole exome sequencing was performed to identify candidate variants, which were subsequently classified according to the ACMG classification guidelines following written informed consent. Structural modeling was subsequently conducted using AlphaFold and PyMOL to evaluate the variant’s impact on protein conformation. Results A Chinese male child presenting with global developmental delay, profound speech impairment, hypotonia, facial dysmorphism, and abnormal brain MRI findings was studied and reported. Trio-based whole exome sequencing identified a novel de novo, ‘likely pathogenic’, missense variant in SPTBN1 (NM_003128.3: c.471 C > G, p.Phe157Leu; Chr2:54612331, GRCh38), located in the actin-binding CH1 domain. In silico analyses suggest this variant disrupts local protein stability through significant side-chain rearrangement (S diff =12.75°), while maintaining overall backbone integrity (RMSD = 0.11 Å). Conclusions This study describes the first genetically confirmed case of DDISBA in a Chinese individual, expands the known phenotypic and genotypic spectrum of SPTBN1-related disorders and highlights the importance of variant type and population diversity in diagnosis. Structural modeling revealing significant side-chain rearrangement and increased steric hindrance suggests that local conformational disruption is a key pathogenic mechanism for the p.Phe157Leu variant.