Dominant variants in PRR12 result in unilateral or bilateral complex microphthalmia

Abstract

Complex microphthalmia is characterized by small eyes with additional abnormalities that may include anterior segment dysgenesis. While many genes are known, a genetic cause is identified in only 4-30% of microphthalmia, with the lowest rate in unilateral cases. We identified four novel pathogenic loss-of-function alleles in PRR12 in families affected by complex microphthalmia and/or Peters anomaly, including two de novo, the first dominantly transmitted allele, as well as the first splicing variant. The ocular phenotypes were isolated with no additional systemic features observed in two unrelated families. Remarkably, ocular phenotypes were asymmetric in all individuals and unilateral (with structurally normal contralateral eye) in three. There are only three previously reported PRR12 variants identified in probands with intellectual disability, neuropsychiatric disorders, and iris anomalies. While some overlap with previously reported cases is seen, nonsyndromic developmental ocular anomalies are a novel phenotype for this gene. Additional phenotypic expansions included short stature and normal development/cognition, each noted in two individuals in this cohort, as well as absence of neuropsychiatric disorders in all. This study identifies new associations for PRR12 disruption in humans and presents a genetic diagnosis resulting in unilateral ocular phenotypes in a significant proportion of cases.

Keywords: PRR12; Peters anomaly; developmental ocular disorder; exome; microphthalmia; unilateral.

Figure 1:. Images from individuals with PRR12 variants.

Facial photographs of Individual 1A (A) with left ocular prosthesis, Individual 1B (B), and Individual 3 (C). Ocular images of Individual 1B showing normal right eye (D) and left eye (G) with mild microphthalmia and Peters anomaly with corneal opacity and iridocorneal adhesion; Individual 2 (E, H, wearing contacts) with bilateral iris coloboma and left Peters anomaly and Individual 3 (F, I) with bilateral Peters anomaly and left microphthalmia.

Figure 2:. Pedigrees and PRR12 variant details.

A. Pedigrees of Families 1–4 with PRR12 genotyping information; Individuals 1A, 1B, 2, 3, 4 are noted on each pedigree and affected individuals are indicated with solid symbols. B. Schematic of PRR12 showing new variants (red arrows) as well as previously reported alterations (black arrows for intragenic variants and X for translocation breakpoint). Genomic structure (exons 1–14, numbered) is displayed above with protein structure indicated below. Protein domains are denoted based on Uniprot Q9ULL5 (Pro-rich 161 – 306; Gly-rich 335 – 685; Pro-rich 764 – 1545; Pro-rich 1666 – 1737).