Systematic genotype-phenotype mapping and transcriptomic analyses highlight SEMA6A as a candidate for neuronal migration defects in 5q22-q23 deletions.

Haploinsufficiency of SEMA6A in 5q22.3-q23.3 deletions, with likely incomplete penetrance; SEMA6A and FLNA are connected within a network through Rho/Rac signaling effectors and co-expressed in apical radial glia and newborn excitatory neurons.

Interstitial deletions of the long arm of chromosome 5 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. The authors report a pediatric patient with a 14.5 Mb interstitial deletion at 5q22.3-q23.3 presenting with global developmental delay, congenital heart defects and bilateral periventricular nodular heterotopia, then 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, two of them with abnormalities potentially relevant to neuronal migration: periventricular nodular heterotopia in their proband and cerebellar vermis hypoplasia in a reference case carrying a focal approximately 452 kb deletion in which SEMA6A was the only haploinsufficiency-intolerant gene. Protein-protein interaction analysis shows that SEMA6A and FLNA, an established periventricular nodular heterotopia gene, are connected within a network through Rho/Rac signaling effectors, and re-analysis of human fetal cortex single-cell RNA sequencing data shows significant co-expression in apical radial glia and newborn excitatory neurons.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The demonstration rests on two informative cases and converging bioinformatic arguments, which makes SEMA6A a credible candidate gene but not yet a disease gene. The practical interest lies elsewhere: when a 5q22.3-q23.3 deletion is found, the presence of SEMA6A within the interval argues for looking for a neuronal migration abnormality on imaging, which changes neurological follow-up well before gene causality is established. The likely incomplete penetrance the authors raise does, however, preclude individual prediction, and genetic counselling should stay cautious on this point.

Analysis by Dr Thibaut Benquey