Name of the disease (synonyms) CUGC for posterior polymorphous corneal dystrophy (PPCD).OMIM# of the disease 122000; 609141; 618031.Name of the analysed genes or DNA/chromosome segments OVOL2 ...(PPCD1); ZEB1 (PPCD3); GRHL2 (PPCD4).OMIM# of the gene(s) 616441; 189909; 608576. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for variants in theOVOL2, ZEB1andGRHL2gene(s) in a diagnostic setting, predictive and parental settings and for risk assesment in relatives.
The aim of this study was to describe the ocular phenotype in a case with Kearns-Sayre syndrome (KSS) spectrum and to determine if corneal endothelial cell dysfunction could be attributed to other ...known distinct genetic causes. Herein, genomic DNA was extracted from blood and exome sequencing was performed. Non-coding gene regions implicated in corneal endothelial dystrophies were screened by Sanger sequencing. In addition, a repeat expansion situated within an intron of
(termed CTG18.1) was genotyped using the short tandem repeat assay. The diagnosis of KSS spectrum was based on the presence of ptosis, chronic progressive external ophthalmoplegia, pigmentary retinopathy, hearing loss, and muscle weakness, which were further supported by the detection of ~6.5 kb mtDNA deletion. At the age of 33 years, the proband's best corrected visual acuity was reduced to 0.04 in the right eye and 0.2 in the left eye. Rare ocular findings included marked corneal oedema with central corneal thickness of 824 and 844 µm in the right and left eye, respectively. No pathogenic variants in the genes, which are associated with corneal endothelial dystrophies, were identified. Furthermore, the CTG18.1 genotype was 12/33, which exceeds a previously determined critical threshold for toxic RNA foci appearance in corneal endothelial cells.
loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder-posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified ...as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in approximately 95% of carriers. In this study, we interrogated in-house exomes (
= 3616) and genomes (
= 88) for the presence of putative heterozygous LoF variants in
. Next, we performed detailed phenotyping in a father and his son who carried a novel LoF c.1279C>T; p.(Glu427*) variant in
(NM_030751.6) absent from the gnomAD v.2.1.1 dataset. Ocular examination of the two subjects did not show any abnormalities characteristic of PPCD3. GnomAD (
= 141,456 subjects) was also interrogated for LoF
variants, notably 8 distinct heterozygous changes presumed to lead to
haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion,
LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of
LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date.
ABSTRACT
Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer ...affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)‐like disease that is common in northern Sweden. Whole‐exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED‐like family linked to a locus on chromosome 10q23‐q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre‐mRNA splicing and is highly likely to be pathogenic. Bi‐allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain‐of‐function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.
A novel missence mutation in the COL17A1 gene, which encodes collagen type XVII alpha 1 was identified as a cause of corneal dystrophy in a large Swedish family. Furthermore, we showed that in a previously reported unrelated family silent COL17A1 variant introduces a cryptic donor site resulting in aberrant premRNA splicing. Our findings highlight importance of COL17A1 mutation analysis in patients with corneal dystrophy.
ABSTRACT
Mutations in the OPN1LW (L‐) and OPN1MW (M‐)cone opsin genes underlie a spectrum of cone photoreceptor defects from stationary loss of color vision to progressive retinal degeneration. ...Genotypes of 22 families with a range of cone disorders were grouped into three classes: deletions of the locus control region (LCR); missense mutation (p.Cys203Arg) in an L‐/M‐hybrid gene; and exon 3 single‐nucleotide polymorphism (SNP) interchange haplotypes in an otherwise normal gene array. Moderate‐to‐high myopia was observed in all mutation categories. Individuals with LCR deletions or p.Cys203Arg mutations were more likely to have nystagmus and poor vision, with disease progression in some p.Cys203Arg patients. Three disease‐associated exon 3 SNP haplotypes encoding LIAVA, LVAVA, or MIAVA were identified in our cohort. These patients were less likely to have nystagmus but more likely to show progression, with all patients over the age of 40 years having marked macular abnormalities. Previously, the haplotype LIAVA has been shown to result in exon 3 skipping. Here, we show that haplotypes LVAVA and MIAVA also result in aberrant splicing, with a residual low level of correctly spliced cone opsin. The OPN1LW/OPN1MW:c.532A>G SNP, common to all three disease‐associated haplotypes, appears to be principally responsible for this mutational mechanism.
Purpose
The aim of the study was to describe the phenotype and molecular genetic causes of X‐linked megalocornea (MGC1). We recruited four British, one New Zealand, one Vietnamese and four Czech ...families.
Methods
All probands and three female carriers underwent ocular examination and Sanger sequencing of the CHRDL1 gene. Two of the probands also had magnetic resonance imaging (MRI) of the brain.
Results
We identified nine pathogenic or likely pathogenic and one variant of uncertain significance in CHRDL1, of which eight are novel. Three probands had ocular findings that have not previously been associated with MGC1, namely pigmentary glaucoma, unilateral posterior corneal vesicles, unilateral keratoconus and unilateral Fuchs heterochromic iridocyclitis. The corneal diameters of the three heterozygous carriers were normal, but two had abnormally thin corneas, and one of these was also diagnosed with unilateral keratoconus. Brain MRI identified arachnoid cysts in both probands, one also had a neuroepithelial cyst, while the second had a midsagittal neurodevelopmental abnormality (cavum septum pellucidum et vergae).
Conclusion
The study expands the spectrum of pathogenic variants and the ocular and brain abnormalities that have been identified in individuals with MGC1. Reduced corneal thickness may represent a mild phenotypic feature in some heterozygous female carriers of CHRDL1 pathogenic variants.
ABSTRACT
Inherited retinal dystrophies are a major cause of childhood blindness. Here, we describe the identification of a homozygous frameshift mutation (c.1194_1195delAG, p.Arg398Serfs*9) in TUB in ...a child from a consanguineous UK Caucasian family investigated using autozygosity mapping and whole‐exome sequencing. The proband presented with obesity, night blindness, decreased visual acuity, and electrophysiological features of a rod cone dystrophy. The mutation was also found in two of the proband's siblings with retinal dystrophy and resulted in mislocalization of the truncated protein. In contrast to known forms of retinal dystrophy, including those caused by mutations in the tubby‐like protein TULP‐1, loss of function of TUB in the proband and two affected family members was associated with early‐onset obesity, consistent with an additional role for TUB in energy homeostasis.
We report the first homozygous mutation in TUB associated with retinal dystrophy and obesity.
Biallelic mutations in AIPL1 cause Leber congenital amaurosis (LCA), a devastating retinal degeneration characterized by the loss or severe impairment of vision within the first few years of life. ...AIPL1 is highly polymorphic with more than 50 mutations and many more polymorphisms of uncertain pathogenicity identified. As such, it can be difficult to assign disease association of AIPL1 variations. In this study, we investigate suspected disease-associated AIPL1 variations, including nonsynonymous missense and intronic variants to validate their pathogenicity.
AIPL1 minigenes harboring missense and intronic variations were constructed by amplification of genomic fragments of the human AIPL1 gene. In vitro splice assays were performed to identify the resultant AIPL1 transcripts.
We show that all nine of the suspected disease-associated AIPL1 variations investigated induced aberrant pre-mRNA splicing of the AIPL1 gene, and our study is the first to show that AIPL1 missense mutations alter AIPL1 splicing. We reveal that the presumed rare benign variant c.784G>A p.(G262S) alters in vitro AIPL1 splicing, thereby validating the disease-association and clarifying the underlying disease mechanism. We also reveal that in-phase exon skipping occurs normally at a low frequency in the retina, but arises abundantly as a consequence of specific AIPL1 variations, suggesting a tolerance threshold for the expression of these alternative transcripts in the retina normally, which is exceeded in LCA.
Our data confirm the disease-association of the AIPL1 variations investigated and reveal for the first time that aberrant splicing of AIPL1 is an underlying mechanism of disease in LCA.
The majority of anterior corneal dystrophies are caused by dominant mutations in TGFBI (transforming growth factor β-induced) collectively known as the epithelial-stromal TGFBI dystrophies. Most ...cases of epithelial basement membrane dystrophy (EBMD) are thought to result from a degenerative (nongenetic) process; however, a minority of cases are associated with specific TGFBI mutations. We evaluated the spectrum of TGFBI mutations and associated phenotypes in a United Kingdom cohort with typical epithelial-stromal TGFBI dystrophies and an EBMD cohort.
We recruited 68 probands with a clinical diagnosis of epithelial-stromal TGFBI dystrophy and 23 probands with bilateral EBMD. DNA was extracted from peripheral leukocytes, and TGFBI was bi-directly Sanger sequenced.
Nine TGFBI mutations were identified. The most common occurred at the mutation hot-spot residues R124 and R555 in 61 probands; these individuals had a genotype-phenotype correlation consistent with prior reports. Four probands with lattice corneal dystrophy carried a mutation in exon 14: p.(A620D), p.(V625D), and p.(H626R). We identified a p.(G623D) mutation in five probands, including two probands from the EBMD cohort. These subjects typically had an onset of severe recurrent corneal epithelial erosion in the fourth decade with mild diffuse or geographic subepithelial corneal opacities and only small anterior stromal lattice structures in older individuals. Symptoms of painful epithelial erosion improved markedly following phototherapeutic keratectomy.
There was a strong correlation between genotype and phenotype for the majority of TGFBI mutations. In this cohort, the p.(G623D) mutation caused a greater proportion of TGFBI-associated disease than anticipated, associated with variable phenotypes including individuals diagnosed with EBMD.
We report the phenotype of a 15-year-old female patient with anterior segment dysgenesis (ASD) caused by a novel heterozygous loss-of-function FOXC1 variant. The proband underwent an ophthalmic ...examination as well as a molecular genetic investigation comprising exome sequencing, a single nucleotide polymorphism array to access copy number and Sanger sequencing to exclude non-coding causal variants. There was bilateral mild iris hypoplasia with pupil deformation and iridocorneal adhesions. In addition to these features of ASD, the corneas were flat, with mean keratometry readings of 38.8 diopters in the right eye and 39.5 diopters in the left eye. There was a snail track lesion of the left cornea at the level of the Descemet membrane. The central corneal endothelial cell density was reduced bilaterally at 1964 and 1373 cells/mm2 in the right and left eyes, respectively. Molecular genetic analysis revealed that the proband was a carrier of a novel heterozygous frameshifting variant in FOXC1, c.605del p.(Pro202Argfs*113). Neither parent had this change, suggesting a de novo origin which was supported by paternity testing. We found no possibly pathogenic variants in the other genes associated with posterior corneal dystrophies or ASD. Further studies are warranted to verify whether there is a true association between snail track lesions, corneal flattening, and pathogenic variants in FOXC1.
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