Variable Expressiveness of a Novel Pathogenic SETD1A Missense Variant Linked to FLOS Domain Haploinsufficiency in a...

Neurodevelopmental disorder, speech impairment, and dysmorphic facies (NEDSID) is an autosomal dominant condition primarily driven by SETD1A haploinsufficiency. While most documented cases are sporadic, genomic mechanisms underlying intrafamilial phenotypic heterogeneity remain poorly understood. This study presents a comprehensive clinical, neurophysiological, and molecular characterization of a two-generation Mexican family segregating a novel heterozygous missense SETD1A variant. Whole-exome sequencing (WES) identified a c.1604G>A (p.Gly535Glu) substitution localized within the critical Functional Location on SETD1A (FLOS) domain, which was validated via automated Sanger sequencing across all family members and 100 ethnically matched controls. The proband exhibited a moderate NEDSID phenotype, including global developmental delay, macrocephaly, borderline IQ (79) with pronounced information-processing deficits, and abnormal EEG sharp waves. Conversely, first-degree relatives carrying the identical variant presented with mild, non-intellectually disabling phenotypes characterized primarily by isolated psychiatric disorders (bipolar disorder, depression) and minimal dysmorphism. Structural 3D modeling and multi-algorithmic in silico profiling confirmed high evolutionary conservation and a deleterious impact (CADD: 22.2, SIFT: 0.00, GERP: 2.924), classifying the variant as a Variant of Uncertain Significance (VUS)/Likely Pathogenic according to ACMG/AMP criteria (PM2, PP1, PP3, PP4). Furthermore, epigenetic dysregulation and chromatin remodeling defects increasingly link these histone-modifier variants to broader psychiatric landscapes. Emerging transcriptomic profiling confirms that dosage-sensitive COMPASS complex disruptions alter downstream neurodevelopmental gene cascades. Our findings present observational evidence of intrafamilial clinical variability in a single pedigree with a SETD1A missense alteration, supporting the hypothesis that non-catalytic domain substitutions may contribute to diverse neurodevelopmental outcomes.