Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report

doi:10.21203/rs.3.rs-24728/v4

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Case report

Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report

https://doi.org/10.21203/rs.3.rs-24728/v4

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Background:

Corneal dystrophies (CDs) are a heterogeneous group of bilateral, genetically determined, non-inflammatory bilateral corneal diseases which are usually limited to the cornea. CD is characterized by a large variability in the age of onset, evolution and visual impact and the accumulation of insoluble deposits at different depths of the cornea. Clinical symptoms revealed bilaterally multiple superficial, epithelial, and stromal anterior granular opacities, in different stages of severity among three patients of this family. 99 genes are involved in CDs.

The aim of this study is to identify pathogenic variant caused atypical corneal dystrophy in a large Moroccan family and to describe the clinical phenotype with their severe different stages of evolution.

Case presentation: In this study, we report a large Moroccan family with CD. Whole Exome Sequencing (WES) was performed in the three affected members who shared a phenotype of a corneal dystrophy in different stages of severity. The variant validation and familial segregation were done by Sanger sequencing in affected sister and mothers and in two unaffected brothers. Whole exome sequencing showed a novel heterozygous mutation (c.1772C>A; p.Ser591Tyr) in TGFBI gene. Clinical examinations demonstrated bilaterally multiple superficial, epithelial and stromal anterior granular opacities; in different stages of severity among three patients of this family.

Conclusions:

This report presents a novel mutation in TGFBI gene, found in three family members affected with different phenotypic aspects. This mutation is associated with Thiel-Behnke corneal dystrophy and therefore, it could be considered as a novel phenotype genotype correlation, which will help in genetic counseling for this family

Medical Genetics

Corneal dystrophy

Thiel-Behnke Corneal Dystrophy

TGFBI gene

Whole Exome Sequencing

Case report

Corneal dystrophy (CDs) are hereditary bilateral primary alterations of the cornea that are not related with prior inflammation or systemic diseases; they mostly appear in the late second decade of progressive evolution (1). Theses alterations have no systemic manifestations and they present with variable shaped corneal opacities impair visual acuity to varying degrees and often have varying results in damage of corneal transparency and serious visual impairment (2). Most corneal dystrophies tend to be autosomal dominant in inheritance, with a high degree of penetrance; few forms are inherited as autosomal recessive traits (3), like the macular corneal dystrophy which is a corneal stromal dystrophy that leads to loss of corneal transparency and decreased vision (4). The most used classification (The IC3D: International Committee for Classification of Corneal Dystrophy), divides CDs into epithelial and subepithelial dystrophy, epithelial-stromal TGFBI dystrophy, stromal dystrophy, and endothelial dystrophy with new genetic, clinical and pathologic information (5, 6). Various genes have been involved in CDs. To our knowledge, 69 disease-associated variants in the transforming growth factor beta-induced gene (TGFBI, OMIM 601692) have been described as involved in different subtypes of CDs in patients. The IC3D classification describes TGFBI-linked dystrophies by the recognition that they affect multiple layers rather than being confined to one corneal layer (7-14).

Several phenotypes have been described according to the corneal layer alteration and the Investigation of pathogenic mutations in the TGFBI gene, with the exception of metabolic affections. Pathogenic mutations in the TGFBI gene have been implicated in various phenotypes depending on the degree of damage to the corneal layer such as Thiel-Behnke Corneal Dystrophy (TBCD, OMIM 602082), Reis-Bucklers Corneal Dystrophy (RBCD, OMIM 608470), Groenouw Granular Corneal Dystrophy type I (CDGG1), Lattice Corneal Dystrophy I and IIIA (LCD1, OMIM 122200 and LCD3A, OMIM 608471) and corneal Dystrophy with Epithelial Basement Membrane (EBMD, OMIM 121820) (15, 16). Such dystrophy is called variant LCD by IC3D conventions (5). Here, we present a novel heterozygous mutation (c.1772C>A; p.Ser591Tyr) in TGFBI gene, using whole exome sequencing within a Moroccan family with CD.

Three patients of a consanguineous family from the south of Morocco were referred to our Department of Medical Genetics at the National of Health in Rabat for Corneal dystrophy. A five generational pedigree diagram was constructed after a thorough interview of the affected mother (III-2), the available three family members affected (IV-7, IV-8 and III-2) including two phenotypically unaffected (IV-1, IV-3). An autosomal dominant mode of inheritance (Fig. 1). Clinical features of patients are given below.

The patient 1 (IV-7) was a 34-year-old woman who complained of recurrent episodes of corneal pain since the age of 18, associated with a decrease in visual acuity. Her vision was 4/10 OD and 6/10 OS. Slit-lamp examinations revealed, in the two eyes, anterior epithelial and stromal corneal dystrophy, in the form of spaced microvacuoles by a heterogeneous thickening of the epithelium due to thickening of an abnormal subepithelial fibrous layer and poorly individualized anterior opacities, with fuzzy edges (Fig. 2). The rest of the examination of the anterior segment is normal, including a normal iris, a clear lens, and an intraocular pressure at 17mmHg in ODG. The Optical Coherence Tomography (OCT) scan shows an unevenness of the epithelial layers by a homogeneous confluent layer of hyper-reflected deposits with a serrated anterior border taking the sawtooth appearance, replacing the Bowman layer and reaching the anterior stroma (Fig. 3 (A , B, C, D)). It is thicker and becomes thinner on the periphery and disappears towards the limb. The pachymetry is 512 μm in OD and 523 μm in OS.

The patient 2 (IV-8) is a woman 44 years old; she presents episodes of recurrent keratitis with a decrease in visual acuity of progressive installation since the age of 20 years. Visual acuity in OD shows that she counts the fingers at 3m / OS at 2/10 (irremovable). Examination with the slit lamp shows in OD and OS anterior epithelial and stromal corneal dystrophy in the form of microvacuoles, especially in the periphery, with a heterogeneous thickening of the epithelium, more pronounced in the center giving a large central opacity with fuzzy edges at both eyes (Fig. 4 (A, B) ). Clear lens; ocular tone at 15 mmHg in OD 14 mmHg in OS, and normal fundus. The OCT of the cornea shows an unevenness of the anterior epithelial and stromal layers with thicker hyper-reflective deposits and a clear central opacity in both eyes (Fig. 5 (A, B, C, D)), As well as a pachymetry at 538 μm in OD, 543 μm in OS.

The patient 3 (III-2) is a woman 72 years old, she has bilateral osteoarthritis, and she reports episodes of recurrent corneal pain. As for her visual acuity, in far vision OD, she can barely see the movement of the fingers / OS: (she counts the fingers at 3m). The Slit lamp examination showed in the right eye, central and paracentric yellowish and gelatinous central and paracentric deposition associated with a corneal opacity deeper than the previous one and affecting the epithelial layers of the Bowman's membrane and the anterior stroma in the form of an epithelial fibrous layer, taking almost the entire corneal surface (Fig. 6). The rest of the examination is hampered by the very important dystrophy of the right eye, (i.e., ineclairable fundus). In the left eye, the slit lamp examination showed CD involving the epithelial layers of the Bowman's membrane and the anterior stroma in the form of a heterogeneous thickening more important at the center, associated with opacity with fuzzy boundaries and a corticonuclear cataract (Fig. 6). In the Fundus, the pupillary glow with flattened retina was noted. The OCT of the cornea shows in the right eye: the form of microvacuoles as thin patches (blue arrows) associated with a significant loss of epithelial cells with disorganization of the epithelial layers, the absence of Bowman's membrane, and an anterior intrastromal bubble (white arrows). The Pachymetry is at 586 μm (Fig. 7). In the Left eye, the OCT shows an irregularity of the corneal surface with disorganization of the epithelial layers, a discontinuous Bowman’s membrane, and anterior stromal reshaping especially in the center (Fig. 7), the process of corneal transplantation, in this patient, is ongoing.

After obtaining written consent from all participants involved in the study, we collected blood samples from family members. Blood samples were collected from five members of the family. The extraction of genomic DNA from whole peripheral blood by using QIAamp DNA Blood Mini Kit (Qiagen Valencia, CA), strictly following the manufacturer’s protocol. Whole-exome sequencing (WES) was performed for the three patients; 500ng of fragmented DNA by enzymatic fragmentation with Kapa Hyper Plus Kit (KapaBiosystems Inc. Wilmington, MA, USA) was amplified according to the manufacturer instructions and was subjected to enrichment with SeqCap EZ Human Exome v3.0 Roche Nimblegen (Roche, Basel, Switzerland).

The Illumina HiSeq 2500 system was used to sequence 64 enriched megabases in a fast-running double-ended mode (2x100bp). Use bcl2fastq v1.8.4 (Illumina) to convert the original data (bcl file) into a fastq file. The sequence was analyzed according to GATK best practice recommendations; BWA-MEM was used for mapping, and GATK (haplotype calling program) was used for variant calling. Adopt Variant Studio (Illumina) for annotation and filtering steps.

Candidate variants were selected using an autosomal dominant mode of inheritance according to the following criteria: i) heterozygous variants, ii) non-synonymous variants, iii) Variants predicted pathogenic or likely pathogenic, iv) Variants with Minor allele frequency (MAF) of <0.01 were selected from the 1000 Genome Project (http://www.1000genomes.org/) and ESP6500 exome project (https://evs.gs.washington.edu/EVS/) and v) segregation analysis. Candidate variants in favor of clinical manifestations and passing the criteria were validated by Sanger sequencing.

The established variants were cross-checked with the 1000 genomes database (http://www.1000genomes.org/), with the Exome Variant Server (http://evs.gs.washington.edu/EVS/), HGMD (http://www.biobase-international. com/product/hgmd) and with the «clinvar» database (http://www.ncbi.nlm.nih.gov/clinvar/).

To confirm the mutation detected by exome sequencing, standard PCR to amplify the exon 10 of TGFBI gene was carried by using the TGFBI_F:5’-GACCAGGCTAATTACCATTCTTG-3’ and TGFBI_R:5’-TGAGATATGTCCTGGAGCCC-3’ primer pair. Amplification products were electrophoresed on 1% agarose gel. Sanger sequencing was performed with dye terminator chemistry (ABI Prism BigDye v3.1) and run on automated sequencer Using 3130 Genetic Analyzer (Thermo Fisher Scientific). The results obtained were aligned with the reference genome (GRCh37/hg19) and then analyzed by DNA variant analysis software (Mutation Surveyor® software).

The transmission form of this family was consistent with an autosomal dominant inheritance (Fig. 1). Clinical examinations demonstrated bilaterally multiple superficial, epithelial and stromal anterior granular opacities; in different stages of severity among three patients of this family. The three patients with the same mutation who shared a mixed phenotype with a superficial form of Granular Corneal Dystrophy (GCD) type 1 and TBCD patterns.

Whole Exome Sequencing and Variant Validation: WES was performed on three family members (IV-7, IV-8 and III-2). The analysis of the data of the three patients shows 30887 variants in 19712 genes. After filtering, this number was reduced to a single allelic variant in the TGFBI gene Filtering of variants is illustrated in Fig. 8. Only a heterozygous mutation (c.1772C>A; p.Ser591Tyr) in the TGFBI gene, identified in these three patients, was proposed as the potential pathogenic mutation within this family. (Fig. 9 A)

Bioinformatics analysis using Polyphen-2 and SIFT suggested that this mutation was predicted to be probably damaging. A high degree of conservation of this amino acid was demonstrated by a score of 5.52 calculated by Genomic Evolutionary Rate Profiling (GERP) http://mendel.stanford.edu/SidowLab/downloads/gerp/index.html. Comparative amino acid sequence alignment of TGFBI across different species revealed that this mutation occurred at highly conserved positions (Fig. 9 B) (https://www.ensembl.org/Homo_sapiens/Tools/Blast). The mutation was confirmed by Sanger sequencing in affected sister and mother and two unaffected brothers.

Furthermore, the variant was not present in the GnomAD browser (accessed July 2020), nor in our in-house WES database of 100 unrelated individuals of Moroccan ethnicity that had been carried out for diseases other than corneal dystrophy.

The genomic and clinical data both supported a diagnosis of Thiel-Behnke corneal dystrophy in this family.

Thiel-Behnke corneal dystrophy was first described in 1967, it is characterized by sub-epithelial honeycomb-shaped corneal opacities in the superficial cornea, progressive visual impairment and autosomal dominant inheritance (17) . Symptoms begin with recurrent corneal erosion during childhood (first and second decade of life) and visual acuity is affected later in life. TBCD can be particularly confused with RBCD during the first two decades of life.

TBCD is in the form of bilaterally cross-linked epithelial opacities in honeycomb in remarkable symmetry with the accumulation of reticular flecks at the level of the Bowman membrane.

Peripheral cornea is typically not involved but can be affected with time in older patients. While RBCD has a geographic-like phenotype, TBCD has a honeycomb-like phenotype. Histopathologically, TBCD is featured by alternating irregular thickening and thinning, and a focal absence of the epithelial basement membrane.

The Bowman layer is replaced by a superficial fibrocellular scar with a pathognomonic wavy sawtoothed pattern or “curly” fibers. The prevalence of TBCD is unknown. Only few Cases have been reported in European population, the United States, Japanese's and other ethnicities, but none in North African population (18, 19). To our knowledge, in the TGFBI gene and in the same position, the mutations (p.Arg555Gln; p.Arg555Trp), have been also reported by Xiang et al and Yu y et al(20, 21) and were correlated with TBCD (7, 22, 23). In this study, we identified a novel mutation in TGFBI gene (c.1772C>A; p.Ser591Tyr). The association of p.Ser591Tyr mutation with TBCD has never been, to our knowledge, reported previously and it is not listed in LOVD v.3.0 (Leiden open variation database). The TGFBI gene is located on chromosome 5q31.1, which codes for a protein of 17 exons composed of 683 amino acids (24, 25). This protein is used for both cell adhesion and the integrin recognition sequence. However that extracellular matrix protein (TGFBIp) contains an EMILIN-like domain rich in N-terminal cysteine, four consecutive and highly homologous domains of fasciclin 1 (FAS1), and a C-terminal arginine-glycine-aspartic, acid motif (26, 27). All pathogenic variants caused in accumulation of insoluble extracellular material in the cornea (28). Accumulation of full length and of fragments of aberrant TGFBIp has been demonstrated in corneal deposits (29). It appears that mutations are also likely to change protein degradation pathways and impact structure and stability of aggregated proteins (24). Most gene TGFBI mutations associated with CD are heterozygous, and some patients with homozygous mutations have a more severe phenotype, indicating that the potential toxic effect has a dose response effect (30). The p.Ser591Tyr mutation is predicted as damaging and is located in the fourth domain (domain Fasc 4). All the TGFBI mutations described, except p.Arg124Cys, are located exactly at the boundary or in this domain. This domain is suspected to have a specific action directly or by interaction with an unknown protein (31).

The two hot spot in the TGFBI gene have been reported associated with the most common corneal dystrophies; the mutation p.Arg555Trp in GCD1 and the mutation p.Arg124His in GCD2. The p.Arg124Cys mutation was reported in LCD1, whereas the p.Arg124Leu mutation was reported in the anterior stromal CD, and the p.Arg555Gln mutation was reported in RBCD (32).

The management of CDs varies with the specific disease. For the treatment of this pathology, corneal transplantation was the recommended treatment, a major limitation being the recurrence of post-transplant corneal deposits, however, some patients are treated with drugs, and others use methods that suggest removing the abnormal layer, like phototherapeutic keratectomy or Deep Anterior Lamellar Keratoplasty (DALK). (27)

Regarding our family case, the chronological evolution of this new dystrophy indicates an early treatment by photokeratectomy in an earlier stage with a promising postoperative result. The particularity in this family is the evolution and the preservation of the posterior layer, which will led to an adapted surgery.

To sum up, we reported in this paper a novel pathogenic mutation of TGFBI gene, which could be a novel phenotype genotype correlation. The clinical and genetic results of our study may further expand the spectrum of TGFBI-linked CDs and may be of great help in genetic counseling for this family.

CD: Corneal dystrophy

WES: Whole Exome Sequencing

IC3D: The International Committee for Classification of Corneal Dystrophies

TGFBI: Transforming growth factor beta induced

TBCD: Thiel-Behnke Corneal Dystrophy

RBCD: Reis-Bücklers Corneal Dystrophies

CDGG1: Groenouw Granular Corneal Dystrophy type I

LCD: Lattice Corneal Dystrophies

EBMD: Corneal Dystrophy with Epithelial Basement Membrane

GCD: Granular Corneal Dystrophy

OCT: Optical Coherence Tomography

FAS1: Fasciclin1

DALK: Deep Anterior Lamellar Keratoplasty.

Ethics approval and consent to participate.

Ethical approval is considered unnecessary according to national provisions. This report was not presented as a research study as all family members were seen in a medical consultation for diagnostic purposes and they gave their written consent to participate and benefit from the molecular analysis

Consent for publication

This family gave written consent for clinical data to be published

Availability of data and materials

All data is contained in the manuscript

Competing interests

The authors declare that there are no conflicts of interest

Funding

Study has no funding source

Authors’ contributions

YB and IC drafted the manuscript and carried out the Sanger study. HT, HE and AB carried diagnostic study and revising the work critically for important intellectual content clinic. MO drafted the manuscript. AZ and JL participated of design of the study and the exome analysis and revised the manuscript. KS and AS participated in the design of the study and in the draft of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We thank the patient’s parents for their gracious participation and support

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Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report

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Abstract

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Background

Case Presentation

Discussion And Conclusions

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