A novel NMD-escaping STAG2 variant associated with syndromic neurodevelopmental delay, growth failure, and distinctive dysmorphism: expanding the phenotype in male patients and literature review

Abstract

We report an 8-year-old male from a consanguineous union presenting with global developmental delay, microcephaly, failure to thrive, and distinctive dysmorphic features (dolichocephaly, triangular face, malar flattening). His elder brother shared similar clinical and dysmorphic findings. The pattern of inheritance within the family (affected male siblings, subtle dysmorphism in mother and consanguinity) prompted consideration of both autosomal recessive and X-linked modes of inheritance. Whole exome sequencing (WES) identified a novel hemizygous STAG2 frameshift variant (NM_001042750.2: c.3688_3689del; p.(Thr1230Hisfs*20)) in both brothers, inherited maternally. The variant is predicted to escape nonsense-mediated decay (NMD), potentially explaining survival, as complete STAG2 loss of function mutations in hemizygous males are most often embryonic lethal. This represents the first report of NMD-escaping STAG2 truncation in living males, expanding the mutational spectrum of STAG2-related disorders. The findings underscore the importance of considering hypomorphic STAG2 variants in males with syndromic neurodevelopmental delay and dysmorphism.