• Female
• Humans
• Adipose Tissue/metabolism
• Liver/metabolism
• Non-alcoholic Fatty Liver Disease/metabolism
• Obesity, Morbid/metabolism

• Skin
• extracellular matrix
• non-structural matrix proteins
• re-epithelialization
• regeneration

Juvenile-onset primary open-angle glaucoma (JOAG), characterized by severe elevation of intraocular pressure and optic neuropathy prior to the age of 40, is a rare subtype of primary open-angle glaucoma. Several genetic mutations have been associated with JOAG.

The proband patient was a young male, diagnosed with primary open-angle glaucoma at the age of 27. The patient and his unaffected parents who have been excluded from classic genetic mutations for primary open-angle glaucoma were included to explore for other possible genetic variants through whole genome sequencing and bioinformatics analysis. In this trio, we found two heterozygous variants inherited from the parents in the proband: c.281G>A, p.Arg94His in OLFM2 and c.177C>G, p.Ile59Met in SIX6. Both genetic mutations are predicted through bioinformatics analysis to replace evolutionary conserved amino acids, therefore rendering a pathogenic effect on proteins. In contrast, very low frequencies for these genetic mutations were recorded in most common control databases.

This is the first report on coinherited mutations of OLFM2 and SIX6 in a JOAG family, which shows the complexity of JOAG inheritance. Large-scale clinical screening and molecular functional investigations on these coinherited mutations are imperative to improve our understanding of the development of JOAG.

• Juvenile-onset primary open-angle glaucoma
• Whole genome sequencing
• Co-inheritance
• OLFM2
• SIX6
• Case report

• Turkey
• consanguinity
• gene
• inherited eye diseases
• ocular genetics

• OLFML3
• Border Collie
• goniodysgenesis
• pectinate ligament abnormality
• pectinate ligament dysplasia
• primary glaucoma

• Border Collie
• eye development
• glaucoma
• goniodysgenesis
• olfactomedin like 3

• Amino Acid Sequence
• Animals
• Anterior Chamber/abnormalities
• Anterior Chamber/metabolism
• Chick Embryo
• Dog Diseases/genetics
• Dog Diseases/metabolism
• Dogs/abnormalities
• Extracellular Matrix Proteins/genetics
• Eye Proteins/genetics
• Female
• Gene Expression Regulation
• Genome-Wide Association Study
• Glaucoma/genetics
• Glaucoma/metabolism
• Glaucoma/veterinary
• Glycoproteins/genetics
• Humans
• Male
• Mice
• Mutation, Missense
• Polymorphism, Single Nucleotide
• Sequence Alignment
• Sequence Analysis, DNA

• BBS/E/D/20320000 Biotechnology and Biological Sciences Research Council
• BB/P013732/1 Biotechnology and Biological Sciences Research Council
• BB/J004316/1 Biotechnology and Biological Sciences Research Council
• BB/J004235/1 Biotechnology and Biological Sciences Research Council

• Animals
• Anterior Eye Segment/abnormalities
• Anterior Eye Segment/physiopathology
• Collagen Type I/genetics
• Collagen Type V/genetics
• Eye Abnormalities/genetics
• Eye Abnormalities/physiopathology
• Eye Diseases, Hereditary/genetics
• Eye Diseases, Hereditary/physiopathology
• Gene Editing
• Gene Expression Regulation, Developmental
• Glaucoma/genetics
• Glaucoma/physiopathology
• Homeodomain Proteins/genetics
• Humans
• Mutation
• Pedigree
• Transcription Factors/deficiency
• Transcription Factors/genetics
• Wnt Signaling Pathway
• Wolff-Parkinson-White Syndrome/genetics
• Zebrafish/genetics
• Zebrafish Proteins/deficiency
• Zebrafish Proteins/genetics
• Homeobox Protein PITX2

• P30 EY001931 NEI NIH HHS
• R01 EY015518 NEI NIH HHS
• T32 EY014537 NEI NIH HHS

• Cataract/genetics
• Cohort Studies
• Connexins/genetics
• Eye Abnormalities/genetics
• Eye Proteins/genetics
• Female
• Gap Junctions/genetics
• Genetic Association Studies/methods
• Heterozygote
• Humans
• Lens, Crystalline/pathology
• Male
• Mutation, Missense/genetics
• Pedigree
• Phenotype

Microphthalmia and anophthalmia (MA) are congenital eye abnormalities that show an extremely high clinical and genetic complexity. In this study, we evaluated the implementation of whole exome sequencing (WES) for the genetic analysis of MA patients. This approach was used to investigate three unrelated families in which previous single‐gene analyses failed to identify the molecular cause.

A total of 47 genes previously associated with nonsyndromic MA were included in our panel. WES was performed in one affected patient from each family using the AmpliSeq^TM Exome technology and the Ion Proton^TM platform.

A novel heterozygous OTX2 missense mutation was identified in a patient showing bilateral anophthalmia who inherited the variant from a parent who was a carrier, but showed no sign of the condition. We also describe a new PAX6 missense variant in an autosomal‐dominant pedigree affected by mild bilateral microphthalmia showing high intrafamiliar variability, with germline mosaicism determined to be the most plausible molecular cause of the disease. Finally, a heterozygous missense mutation in RBP4 was found to be responsible in an isolated case of bilateral complex microphthalmia.

This study highlights that panel‐based WES is a reliable and effective strategy for the genetic diagnosis of MA. Furthermore, using this technique, the mutational spectrum of these diseases was broadened, with novel variants identified in each of the OTX2,PAX6, and RBP4 genes. Moreover, we report new cases of reduced penetrance, mosaicism, and variable phenotypic expressivity associated with MA, further demonstrating the heterogeneity of such disorders.

• Anophthalmia
• microphthalmia
• ophthalmology
• whole exome sequencing