Trio exome sequencing of an optic nerve hypoplasia cohort reveals evidence for polygenic architecture

Optic nerve hypoplasia (ONH), the leading congenital cause of permanent blindness, is characterized by a retinal ganglion cell (RGC) deficit at birth and frequently associated neurologic and endocrine abnormalities. Multifactorial developmental events are hypothesized to underlie ONH; however, environmental influences are unclear, and genetic causes are under-investigated.

To identify monogenic, disease-causing variants among ONH patients, exomes from 34 ONH subjects and their parents were sequenced and rare variants identified. Inheritance-modelled variants were evaluated using population frequency, pathogenicity predictions, and mutational constraint metrics. Variants with the strongest genetic effect lacked evidence that they are monogenic and causal. All rare variants were filtered using mutational constraint metrics and pathogenicity predictions. The resultant variant-harboring genes were examined for recurrence within the cohort, gene ontology over-representation, RGC expression, and coincidence with neuro developmental disorder (NDD), autism, and previously proposed ONH genes.

Mutationally constrained genes with potentially pathogenic mutations were enriched in gene ontologies related to neuro developmental processes, were expressed in RGCs at significantly higher levels than random exome variant genes, and were enriched in autism and NDD-associated genes. Including the genes with strong genetic effect variants, these analyses call attention to 161 genes with potentially pathogenic variants that may contribute polygenic risk for ONH.