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

Abstract

Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harbored the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.

Keywords: MFRP; MYRF; PRSS56; TMEM98; axial length; microphthalmia; nanophthalmos; posterior microphthalmos.

Figure 1:. Genetic characterisation of a nanophthalmos and posterior microphthalmos cohort.

(A) Self-reported ancestry of the 13 probands. (B) Proportion of probands with suspected pathogenic variants in the indicated genes. (C) Pedigrees grouped by affected gene. Asterisks indicate previously reported pedigrees. (D) Schematic of loci and variants identified. (E) Protein schematics with variants identified. C, cytoplasmic domain; TM, transmembrane domain; CUB, Complement C1r/C1s, Uegf, Bmp1 domain; L, LDL-receptor class A domain; FZ, frizzled domain; CC, coiled-coil domain.

Figure 2:. Origins of PRSS56 c.1066dupC in a mutational hotspot.

(A) PRSS56 protein schematic with variants identified in this study (white circles), or previous studies (coloured circles). Dashed vertical lines indicate exon boundaries. (B) Haplotype structure surrounding the PRSS56 c.1066dupC variant in a previously reported Tunisian founder, and two unrelated probands. (C) Frequency of PRSS56 loss-of-function variants (nonsense, essential splice, frameshift) reported in gnomAD r2.0.2 and Bravo (TOPMed Freeze5) collections. The c.1066dupC variant is highlighted in red. (D) Frequency of c.1066dupC across multiple ancestries within gnomAD. (E) IGV representation of the left-shifted c.1066dupC variant within a cytosine mononucleotide repeat.

Figure 3:. Clinical and transcriptional phenotypes of dominant and recessive forms of nanophthalmos.

Mean ocular axial length (A) and spherical equivalent (B) of affected individuals stratified by genetic diagnosis. For both phenotypes, group means were significantly different by one-way ANOVA (P<0.0005), with asterisks (*) indicating a significant difference from the unsolved cohort (Tukey multiple comparison testing, P<0.03). (C) Relative mean expression dendrogram (normalised log counts per kb per million mapped reads) of genes in dissected human adult cadaveric eye tissue. S, sclera; CS, corneal stroma; CE, corneal epithelium; TM, trabecular meshwork; DM, Descemet’s membrane; ON, optic nerve; ONH, optic nerve head; PI, peripheral iris; CB, ciliary body.