Distinct genetic etiologies with overlapping neurodevelopmental phenotypes: a two-case series involving GNAI1 and CHAMP1 variants

Background Neurodevelopmental disorders (NDDs) comprise a genetically heterogeneous group of conditions characterized by global developmental delay, epilepsy and behavioral abnormalities. Advances in next-generation sequencing have expanded the number of genes implicated in NDDs, including GNAI1 and CHAMP1 , which act through distinct molecular pathways yet may produce overlapping phenotypes. Case Presentation: We describe two unrelated boys with severe developmental delay and hypotonia but without epilepsy. Case 1 involved a 4-year-old with marked axial hypotonia and distal hypertonia mimicking dystonic–spastic cerebral palsy. Whole-exome sequencing identified a de novo heterozygous GNAI1 variant (c.118G > C; p.Gly40Arg). Case 2 involved a 6-year-old with global hypotonia, autistic features, and mild dysmorphism who achieved independent walking. Exome analysis revealed a novel heterozygous nonsense CHAMP1 variant (c.736G > T; p.Glu246*), not previously reported in ClinVar or gnomAD. In both cases, speech was absent. Conclusions : Despite distinct molecular mechanisms—impaired G-protein signaling in GNAI1 and haploinsufficiency in CHAMP1 —both cases shared early hypotonia, developmental delay, and absent speech. These cases expand the clinical spectrum of GNAI1 - and CHAMP1 -related disorders and underscore the importance of early genomic investigation in children with unexplained developmental delay, even in the absence of epilepsy or structural brain abnormalities