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.

ARHGAP35 is a novel factor disrupted in human developmental eye phenotypes

“…One of the others was inherited from an affected parent-while it could not be conclusively proven to be de novo, it was not present in five unaffected family members. Interestingly, in this family both affected individuals had a unilateral ocular phenotype, similar to the recently reported PRR12 gene with dominant unilateral MAC or ASD phenotypes [22]. In the final case, the variant was inherited from a parent without MAC but with reduced vision that required corrective lenses.…”

Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

“…A very recent report documents four additional truncating PRR12 variants in a cohort of individuals with microphthalmia/anophthalmia/coloboma, further supporting the impact of PRR12 loss in eye development. 21 The microdeletion observed in patient 24 resulted in the heterozygous loss of 146 annotated genes, 86 of which are listed in OMIM, and 15 of which have associated disease phenotypes. However, only 2 of these 15 genes are seemingly highly intolerant of loss-of-function changes: NUP62 (pLI: 0.95) and PPP2R1A (pLI: 0.98).…”

“…Written informed consent was obtained from all patients in accordance with protocols approved by the appropriate human subject ethics committees: through Baylor College of Medicine for patients 7,8,12,17,18,19,21,22,23, and 24 and through their respective academic/health sciences center for the rest of the cohort. Consents for publication of photographs were attained from parents/legal guardians of patients 1, 3, 8, 10, 11, 12, 14, 16, 18, 19, 20, and 24.…”

First implication of MIP in bilateral microphthalmia with persistent fetal vasculature

“…Indeed, as for other ocular malformations such as micro‐anophthalmia (Plaisancié et al, 2019), the probability of finding a pathogenic variant is higher when the ocular feature is bilateral, severe, and associated with extra‐ocular features. Disease‐causing variants in ocular development genes have been occasionally described in non‐syndromic ( ATOH7 , PAX6 , PRR12 , …) (Azuma et al, 2003; Prasov et al, 2012; Reis et al, 2020) and syndromic ( CTNNB1, CRPPA , NF2 , NDP , …) (Aponte et al, 2009; Bayram et al, 2021; Nguyen et al, 2005; Taylor et al, 2022) forms of PFV, but part of these associations are case reports that needs to be replicate. PFV and chromosomal abnormalities have also been occasionally associated (trisomy 13, 6p duplication, …) (Goldberg, 1997; Su et al, 2012).…”

“…Disease-causing variants in ocular development genes have been occasionally described in non-syndromic (ATOH7, PAX6, PRR12, …) (Azuma et al, 2003;Prasov et al, 2012;Reis et al, 2020) and syndromic (CTNNB1, CRPPA, NF2, NDP, …) (Aponte et al, 2009;Bayram et al, 2021;Nguyen et al, 2005;Taylor et al, 2022) forms of PFV, but part of these associations are case reports that needs to be replicate. PFV and chromosomal abnormalities have also been occasionally associated (trisomy 13, 6p duplication, …) (Goldberg, 1997;Su et al, 2012).…”