The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort

Nanophthalmos and posterior microphthalmos are ocular abnormalities in which botheyes are abnormally small, and typically associated with extreme hyperopia. We rec-ruited 40 individuals from 13 kindreds with nanophthalmos or posteriormicrophthalmos, with 12 probands subjected to exome sequencing. Nine probands(69.2%) were assigned a genetic diagnosis, with variants inMYRF,TMEM98,MFRP,andPRSS56. Two of fourPRSS56families harbored the previously describedc.1066dupC variant implicated in over half of all reportedPRSS56kindreds, withdifferent surrounding haplotypes in each family suggesting a mutational hotspot. Indi-viduals with a genetic diagnosis had shorter mean axial lengths and higher hyperopiathan those without, with recessive forms associated with the most extreme pheno-types. These findings detail the genetic architecture of nanophthalmos and posteriormicrophthalmos in a cohort of predominantly European ancestry, their relative clinicalphenotypes, and highlight the shared genetic architecture of rare and common disor-ders of refractive error.