PKHD1, the gene primarily mutated in human autosomal recessive polycystic kidney disease, is one of the top 20 genes associated with primary open angle glaucoma (POAG) and associated endophenotypes in Genome-Wide Association Studies. Here, we show that Pkhd1 del3-67/del3-67 mutant mice develop congenital glaucoma due to anterior segment dysgenesis. Using a combination of genetic, epigenetic, bioinformatics and mouse developmental biology approaches, we show that Pkhd1 del3-67/del3-67 mice lack Tfap2b and AP-2β expression in a subset of periocular mesenchymal cells at E13.5 and its derivatives. Our data suggest that the Pkhd1 del3-67 deletion disrupts features of the Pkhd1-Tfap2b genomic architecture essential for Tfap2b cell-specific activities. Consistent with this model, Pkhd1 del3-67/+ ;Tfap2b ko/+trans-heterozygotes lack Tfap2b and AP-2β in relevant cell-types and have similar eye abnormalities as neural crest cell-specific Tfap2b ko mutants. These findings provide a likely causal explanation for how SNPs associated with PKHD1 are functionally linked to POAG and add insight into understanding the complexity of disease-causing SNP associations and gene regulatory mechanisms.

Albinism classically encompasses several forms: oculocutaneous (OCA), ocular (OA1 and Foveal hypoplasia optic nerve decussation defect anterior segment dysgenesis syndrome [FHONDA]), and syndromic (Hermansky-Pudlak syndrome [HPS], Chediak-Higashi syndrome [CHS]), with all being autosomal recessive except X-linked recessive OA1. Twenty-one genes are identified to date, with OCA1 being most common in Europeans or patients of European descent and OCA2 in Sub-Saharan Africans. Their sequencing provides a diagnostic rate of ∼70 %, though unresolved cases may arise from variants in poorly explored non-coding regions, undetected genes, or differential diagnoses. The cellular and molecular mechanisms underlying non-syndromic forms of albinism affect the ability of pigment cells to synthesize melanin pigments in melanosomes, mainly through defects in melanogenic enzymes, or in ion channels or transporters affecting melanosome pH regulation. In contrast, syndromic forms of albinism (e.g., HPS subtypes) are membrane trafficking disorders caused by mutations in multi-subunit protein complexes (e.g., BLOC1, BLOC2, BLOC3, or AP-3) targeting the formations and functions of certain lysosome-related organelles (LROs), of which the melanosome is a prototypical member. Integrating clinical, genetic and fundamental research is essential for a comprehensive understanding of albinism, from patient manifestations to identifying molecular targets and elucidating their cell and tissue-specific functions, ultimately paving the way for improved diagnostics and therapeutic strategies.

Phenotypic and genotypic heterogeneity in congenital ocular diseases, especially in anterior segment dysgenesis (ASD), have created challenges for proper diagnosis and classification of diseases. Over the last decade, genomic research has indeed boosted our understanding in the molecular basis of ASD and genes associated with both autosomal dominant and recessive patterns of inheritance have been described with a wide range of expressivity. Here we describe the molecular characterization of a cohort of 162 patients displaying isolated or syndromic congenital ocular dysgenesis. Samples were analyzed with diverse techniques, such as direct sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing (WES), over 20 years. Our data reiterate the notion that PAX6 alterations are primarily associated with ASD, mostly aniridia, since the majority of the cohort (66.7%) has a pathogenic or likely pathogenic variant in the PAX6 locus. Unexpectedly, a high fraction of positive samples (20.3%) displayed deletions involving the 11p13 locus, either partially/totally involving PAX6 coding region or abolishing its critical regulatory region, underlying its significance. Most importantly, the use of WES has allowed us to both assess variants in known ASD genes (i.e., CYP1B1, ITPR1, MAB21L1, PXDN, and PITX2) and to identify rarer phenotypes (i.e., MIDAS, oculogastrointestinal-neurodevelopmental syndrome and Jacobsen syndrome). Our data clearly suggest that WES allows expanding the analytical portfolio of ocular dysgenesis, both isolated and syndromic, and that is pivotal for the differential diagnosis of those conditions in which there may be phenotypic overlaps and in general in ASD.

Biallelic MAB21L1 variants have been reported to cause autosomal recessive cerebellar, ocular, craniofacial, and genital syndrome (COFG), whereas only five heterozygous pathogenic variants have been suspected to cause autosomal dominant (AD) microphthalmia and aniridia in eight families. This study aimed to report an AD ocular syndrome (blepharophimosis plus anterior segment and macular dysgenesis [BAMD]) syndrome based on clinical and genetic findings from patients with monoallelic MAB21L1 pathogenic variants in our cohort and reported cases. Potential pathogenic variants in MAB21L1 were detected from a large in-house exome sequencing dataset. Ocular phenotypes of the patients with potential pathogenic variants in MAB21L1 were summarized, and the genotype-phenotype correlation was analyzed through a comprehensive literature review. Three heterozygous missense variants in MAB21L1, predicted to be damaging, were detected in 5 unrelated families, including c.152G>T in 2, c.152G>A in 2, and c.155T>G in one. All were absent from gnomAD. The variants were de novo in two families, transmitted from affected parents to offspring in two families, and with an unknown origin in the other family, demonstrating strong evidence of AD inheritance. All patients revealed similar BAMD phenotypes, including blepharophimosis, anterior segment dysgenesis, and macular dysgenesis. Genotype-phenotype analysis suggested that patients with monoallelic MAB21L1 missense variants had only ocular anomalies (BAMD), whereas patients with biallelic variants presented both ocular and extraocular symptoms. Heterozygous pathogenic variants in MAB21L1 account for a new AD BAMD syndrome, which is completely different from COFG caused by homozygous variants in MAB21L1. Nucleotide c.152 is likely a mutation hot spot, and the encoded residue of p.Arg51 might be critical for MAB21L1.

Peters anomaly is characterized by a defect in the development of the anterior segment of the eye during fetal development (Anterior segment dysgenesis). This anomaly presents a broad clinical presentation ranging from minimal peripheral corneal opacity to extensive adhesions of the iris and lens with dense central corneal opacity that impairs vision. Peters Plus Syndrome is a recessive autosomal syndrome manifested by Peters anomaly, along with systemic disorders such as brachydactyly (short fingers and toes), short stature, a developmental delay, dysmorphic facial features, and may accompanied with heart and genitourinary malformations. The most common sign of Peters' anomaly is corneal opacity that appears at birth. This opacity can cause blockage of the central visual axis and cause the development of a deprivational amblyopia. In addition, the patient may suffer from glaucoma due to malformations in the angle structures as well as a shallow anterior chamber. Treatments are aimed at clearing the central visual axis as soon as possible in order to allow the visual system to mature and to avoid the development of amblyopia. Full-thickness corneal transplantation combined with Cataract surgery if necessary is the current standard of care. Optical iridoplasty is a milder surgical alternative in cases where the corneal opacity is not significant.