Compound heterozygous mutations in TGFBI cause a severe phenotype of granular corneal dystrophy type 2

Abstract

We investigated the clinical and genetic features of patients with severe phenotype of granular corneal dystrophy type 2 (GCD2) associated with compound heterozygosity in the transforming growth factor-β-induced (TGFBI) gene. Patients with severe GCD2 underwent ophthalmic examination (best-corrected visual acuity test, intraocular pressure measurement, slit-lamp examination, and slit-lamp photograph analysis) and direct Sanger sequencing of whole-TGFBI. The patient’s family was tested to determine the pedigrees. Five novel mutations (p.(His174Asp), p.(Ile247Asn), p.(Tyr88Cys), p.(Arg257Pro), and p.(Tyr468*)) and two known mutations (p.(Asn544Ser) and p.(Arg179*)) in TGFBI were identified, along with p.(Arg124His), in the patients. Trans-phase of TGFBI second mutations was confirmed by pedigree analysis. Multiple, extensive discoid granular, and increased linear deposits were observed in the probands carrying p.(Arg124His) and other nonsense mutations. Some patients who had undergone phototherapeutic keratectomy experienced rapid recurrence (p.(Ile247Asn) and p.(Asn544Ser)); however, the cornea was well-maintained in a patient who underwent deep anterior lamellar keratoplasty (p.(Ile247Asn)). Thus, compound heterozygosity of TGFBI is associated with the phenotypic variability of TGFBI corneal dystrophies, suggesting that identifying TGFBI second mutations may be vital in patients with extraordinarily severe phenotypes. Our findings indicate the necessity for a more precise observation of genotype–phenotype correlation and additional care when treating TGFBI corneal dystrophies.

Corneal histomorphology and electron microscopic observation of R124L mutated corneal dystrophy in a relapsed pedigree

“…The gene mutation of CD and the pathological changes of cornea have been reported previously [2,16] . This paper is the first to report the pathological changes and TEM ultrastructure of the corneal graft with recurrent CD.…”

“…C orneal dystrophy (CD) with R124L mutation is a familial, primary, binocular autosomal dominant genetic disease [1][2] . According to the 2015 International Classification of Corneal Dystrophies (IC3D) and based on the affected R124L mutated CD morphology in relapsed pedigree Int J Ophthalmol, Vol.…”

Mini-Review: Clinical Features and Management of Granular Corneal Dystrophy Type 2

“…Genome editing technique such as CRISPR/Cas9 may be used to target genes site specifically. However, one of the problems of using gene therapy technique is the unwanted off-target effects, which may affect or silence the opposite normal allele or other genes [ 31 , 76 ]. Developing safe delivery methods free from unwanted off-target effects would be essential for specifically targeted gene therapy for GCD2.…”

“…Severity of heterozygote GCD2 can vary among the patients [9,10,[21][22][23][24][25][26][27][28][29][30]. Several severe phenotypic forms were found to be caused by different types of compound heterozygous mutation [31].…”