Characterization of a novel non‐canonical splice site variant (c.886‐5T>A) in NBAS and description of the associated phenotype. Issue 3 (8th December 2022)

• Record Type: Journal Article
• Authors: Priglinger, Claudia S.; Rudolph, Günter; Schmid, Irene; Mazzola, Pascale; Haack, Tobias B.; Reith, Milda; Stingl, Katarina; Weisschuh, Nicole
• Is Part Of: Molecular genetics & genomic medicine. Volume 11:Issue 3(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-08
• Subjects: cone dystrophy -- NBAS -- non‐canonical splice site variant -- optic atrophy -- RNA analysis -- SOPH syndrome; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.2120
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Biallelic pathogenic variants in the neuroblastoma‐amplified sequence ( NBAS ) gene manifest in a broad spectrum of disorders, including, but not limited to recurrent acute liver failure, skeletal dysmorphism, susceptibility to infections, and SOPH syndrome with its cardinal symptoms of short stature, optic atrophy, and Pelger–Huët anomaly. We aimed to present clinical and genetic characteristics of two sisters (20 and 15 years old) who were diagnosed with optic atrophy and cone dystrophy in childhood. Genome sequencing revealed two novel variants in NBAS in compound heterozygous state in both sisters, namely a 1‐bp deletion predicted to result in a premature termination codon (c.5104del; p.(Met1702*)), and a non‐canonical splice site variant of unclear significance (c.886‐5T>A; p.?). Results: Clinical examination and history revealed cone dystrophy, optic atrophy, and Pelger–Huët anomaly, but no short stature, recurrent acute liver failure, or susceptibility to infections. RNA analysis revealed that the c.886‐5T>A variant results in two aberrant transcripts that are predicted to lead to in frame amino acid changes in the β‐propeller region of the protein. Conclusion: We hypothesize that the phenotype of our subjects, which appears to be at the end of the spectrum of NBAS ‐related disorders, could be explained by residual protein function mediated by the non‐canonical splice site variant c.886‐5T>A. Our study contributes to the existing knowledge on the genotypic and phenotypic spectrum of NBAS ‐related disorders. Abstract : Genome sequencing revealed two novel variants in the neuroblastoma‐amplified sequence (NBAS) gene in compound heterozygous state in two sisters diagnosed with optic atrophy and cone dystrophy, namely a 1 bp deletion predicted to result in a premature termination codon (c.5104del; p.(Met1702*)), and a non‐canonical splice site variant of unclear significance (c.886 5T>A; p.?). We demonstrated that the c.886 5T>A variant results in two aberrant transcripts that are predicted to lead to in frame amino acid changes in the β‐propeller region of the protein.