A novel homozygous ZNF469 variant causing brittle cornea syndrome is associated with corneal ectasias in heterozygous carriers.

AIM: To describe a family segregating a novel truncating ZNF469 homozygous mutation causing brittle cornea syndrome type 1 in a male patient and associated with corneal ectasia in his two heterozygous young children. METHODS: A 49-year-old affected male and his 12- and 8-year-old, apparently healthy, siblings underwent phenotypic and genetic assessment. An Oculus Pentacam Scheimpflug topographer system was employed for keratometries and central corneal thickness measurements. Exome sequencing was performed in DNA from the index case with subsequent Sanger sequencing confirmation of the ZNF469 gene causal variant in his relatives. RESULTS: The index case had a history of bilateral keratoglobus, corneal perforations, bilateral hypoacusia, and skeletal anomalies. His two children exhibited topographic anomalies compatible with keratoconus suspects as well as mild skeletal anomalies. Genetic analysis identified a novel homozygous c.2340delC variant in the ZNF469 gene, which predicts a p.(Arg781Glufs*19) truncated protein. Sanger sequencing identified heterozygosity for the c.2340delC variant in DNA from both siblings. CONCLUSION: Our results expand the mutational spectrum associated with brittle cornea syndrome and provide the first demonstration of early corneal anomalies in subjects carrying monoallelic ZNF469 variants.

Familial fleck corneal dystrophy caused by complete deletion of the PIKFYVE gene.

BACKGROUND: Fleck corneal dystrophy (FCD) is a rare autosomal dominant disease that affects exclusively the corneal stroma. The disease is caused by heterozygous variants in PIKFYVE, a gene encoding a lipid kinase involved in multiple cellular pathways, primarily participating in membrane dynamics and signaling. This report describes a familial case of FCD caused by a complete deletion of the PIKFYVE gene. MATERIAL AND METHODS: A clinical ophthalmic examination was performed on the proband and family members. Genetic testing included next-generation sequencing (multigene panel), and chromosomal microarray analysis. A quantitative PCR assay was designed in order to segregate the deletion. RESULTS: A 19-year-old male, with no family or personal history of ocular disease, presented for evaluation due to an acute illness consisting of burning, foreign body sensation, and red eye. Slit lamp biomicroscopy revealed bilateral small pterygia and scattered bilateral white opacities in the corneal stroma, a very similar corneal phenotype was found in the 47-year-old father, who was asymptomatic. NGS detected a heterozygous deletion of the entire PIKFYVE coding sequence. CMA in DNA from the propositus indicated a 543 kb deletion in 2q33.3q34 spanning the entire PIKFYVE gene. The deletion was confirmed in the father. CONCLUSIONS: We add to the molecular spectrum of FCD by describing a familial case of a whole PIKFYVE gene deletion in affected subjects. Our findings support that normal expression of PIKFYVE is necessary for corneal keratocytes homeostasis and normal corneal appearance. We conclude that PIKFYVE haploinsufficiency is the molecular mechanism underlying this familial case of FCD.

Detailed phenotypic description of stromal corneal dystrophy in a large pedigree carrying the uncommon TGFBI p.Ala546Asp pathogenic variant.

PURPOSE: The purpose of this study is to describe the corneal clinical spectrum and the intrafamilial phenotypic differences in an extended pedigree suffering from stromal corneal dystrophy due to the rare p.Ala546Asp mutation in TGFBI. METHODS: A total of 15 members from a four-generation Mexican family were ascertained for clinical and genetic assessment. All individuals underwent slit-lamp biomicroscopic examination and an extensive ophthalmological examination including corneal topography (OCULUS Pentacam® AXL), corneal biomechanics (OCULUS Corvis ST), and corneal confocal biomicroscopy (Heidelberg Engineering®). A total of 10 individuals carried the heterozygous c.1637C>A (p. Ala546Asp) mutation at TGFBI exon 12. RESULTS: Nine out of 10 mutation positive patients were available for clinical characterization. The mean age was 35.5 years, with the youngest and the eldest ones being 3 years old and 62 years old, respectively. The median age of onset of the symptoms was 19.7 years. Five (55.6%) patients presented with a predominantly granular corneal dystrophy type 2 (GCD2) phenotype, one presented with a lattice corneal dystrophy (LCD) phenotype, and one with a granular corneal dystrophy type 1 (GCD1) phenotype. Interestingly, two mutation positive subjects had no clinical deposits in the cornea, demonstrating incomplete penetrance of the disorder in this family. CONCLUSIONS: Clinical differences in corneal phenotypes within this CD family and with other pedigrees carrying the same TGFBI genetic defect could be explained by the age of clinical examination of individual patients and/or by the presence of genetic and/or environmental modifiers.

Novel CHRDL1 mutation causing X-linked megalocornea in a family with mild anterior segment manifestations in carrier females.

PURPOSE: X-linked megalocornea (XMC) is a rare anterior segment malformation characterized by a nonprogressive enlargement of the cornea to 13 mm or greater in the setting of normal intraocular pressure. XMC is caused by mutations in the CHRDL1 gene and it is inherited as an X-linked recessive trait affecting only males. Here, we describe the results of phenotypic and genetic assessment in a novel XMC pedigree. METHODS: Three subjects (a father and his two daughters) underwent a complete clinical and imaging ocular examination including biomicroscopy, fundoscopy, tonometry, visual acuity, Pentacam Scheimpflug imaging, anterior segment Swept Source OCT, and ultrabiomicroscopy. Genetic analysis was performed through whole exome sequencing in 3 family members. Candidate variants were validated by sanger sequencing. RESULTS: The affected father exhibited megalocornea, very deep anterior chambers, retrocorneal pigmentation, iris atrophy, queer iris configuration, extremely open iridocorneal angles, and cataracts. Notably, both daughters showed queer iris configuration and abnormally widely open iridocorneal angles in both eyes. Genetic analysis identified a novel hemizygous c.207+1G>A splicing variant in CHRDL1 in the affected father. Both mildly affected daughters were heterozygous for the pathogenic variant. CONCLUSIONS: Here, we report an additional XMC family due to a novel mutation in the CHRDL1 gene. Mild anterior segment anomalies were observed in two heterozygous carriers demonstrating for the first time a CHRDL1-linked phenotype in females. A detailed comparison of the clinical and genetic features of this pedigree with those observed in previously published XMC cases is also presented.