Systematic genotype-phenotype mapping and transcriptomic analyses highlight SEMA6A as a candidate for neuronal...

Interstitial deletions of the long arm of chromosome 5 (5q) are rare and associated with variable neurodevelopmental features. While proximal deletions involving APC are well-characterized, the genetic basis of structural brain malformations in this region remains poorly defined. Here, we report a pediatric patient with a 14.5 Mb interstitial deletion at 5q22.3-q23.3 who presented with global developmental delay, congenital heart defects, and bilateral periventricular nodular heterotopia. To identify candidate genes that may contribute to structural brain malformations in this interval, we conducted a systematic genotype-phenotype analysis of 64 cases compiled from the literature and the DECIPHER database. Structural brain malformations were identified in four cases. Of these, two involved developmental brain abnormalities with potential relevance to neuronal migration: periventricular nodular heterotopia in our proband and cerebellar vermis hypoplasia in a reference case carrying a focal ~452 kb deletion in which SEMA6A was the only haploinsufficiency-intolerant gene. This convergence pointed to SEMA6A as a candidate contributor to migration-related brain abnormalities. We further examined the relationship between SEMA6A and FLNA, an established disease gene for periventricular nodular heterotopia. Protein-protein interaction analysis revealed that SEMA6A and FLNA are connected within a network through Rho/Rac signaling effectors. Furthermore, re-analysis of human fetal cortex single-cell RNA sequencing data demonstrated that SEMA6A and FLNA are significantly co-expressed in apical radial glia and newborn excitatory neurons. These findings suggest that SEMA6A is a candidate contributor to neuronal migration defects in 5q22.3-q23.3 deletions, likely exhibiting incomplete penetrance.