Extending the spectrum of CLRN1- and ABCA4-associated inherited retinal dystrophies caused by novel and recurrent variants using exome sequencing

Mohammed Abu-Ameerh; Hashim Mohammad; Zain Dardas; Raghda Barham; Dema Ali; Maysa Bijawi; Mohamed Tawalbeh; Sami Amr; Ma'mon M Hatmal; Muawyah Al-Bdour; Abdalla Awidi; Belal Azab

doi:10.1002/mgg3.1123

Extending the spectrum of CLRN1- and ABCA4-associated inherited retinal dystrophies caused by novel and recurrent variants using exome sequencing

Mol Genet Genomic Med. 2020 Mar;8(3):e1123. doi: 10.1002/mgg3.1123. Epub 2020 Jan 22.

Authors

Mohammed Abu-Ameerh¹, Hashim Mohammad², Zain Dardas³, Raghda Barham⁴, Dema Ali⁴, Maysa Bijawi⁴, Mohamed Tawalbeh⁵, Sami Amr⁶, Ma'mon M Hatmal⁷, Muawyah Al-Bdour¹, Abdalla Awidi^{4

8}, Belal Azab^{3

9}

Affiliations

¹ Department of Ophthalmology, Jordan University Hospital, The University of Jordan, Amman, Jordan.
² School of Medicine, The University of Jordan, Amman, Jordan.
³ Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, Jordan.
⁴ Cell Therapy Center, The University of Jordan, Amman, Jordan.
⁵ Department of Otolaryngology, Jordan University Hospital, The University of Jordan, Amman, Jordan.
⁶ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, The Hashemite University, Zarqa, Jordan.
⁸ Department of Medicine and Hematology, Jordan University Hospital, The University of Jordan, Amman, Jordan.
⁹ Human and Molecular Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA.

Abstract

Background: Inherited retinal dystrophies (IRDs) are characterized by extreme genetic and clinical heterogeneity. There are many genes that are known to cause IRD which makes the identification of the underlying genetic causes quite challenging. And in view of the emergence of therapeutic options, it is essential to combine molecular and clinical data to correctly diagnose IRD patients. In this study, we aimed to identify the disease-causing variants (DCVs) in four consanguineous Jordanian families with IRDs and describe genotype-phenotype correlations.

Methods: Exome sequencing (ES) was employed on the proband patients of each family, followed by segregation analysis of candidate variants in affected and unaffected family members by Sanger sequencing. Simulation analysis was done on one novel CLRN1 variant to characterize its effect on mRNA processing. Clinical evaluation included history, slit-lamp biomicroscopy, and indirect ophthalmoscopy.

Results: We identified two novel variants in CLRN1 [(c.433+1G>A) and (c.323T>C, p.Leu108Pro)], and two recurrent variants in ABCA4 [(c.1648G>A, p.Gly550Arg) and (c.5460+1G>A)]. Two families with the same DCV were found to have different phenotypes and another family was shown to have sector RP. Moreover, simulation analysis for the CLRN1 splice donor variant (c.433+1G>A) showed that the variant might affect mRNA processing resulting in the formation of an abnormal receptor. Also, a family that was previously diagnosed with nonsyndromic RP was found to have Usher syndrome based on their genetic assessment and audiometry.

Conclusion: Our findings extend the spectrum of CLRN1- and ABCA4-associated IRDs and describe new phenotypes for these genes. We also highlighted the importance of combining molecular and clinical data to correctly diagnose IRDs and the utility of simulation analysis to predict the effect of splice donor variants on protein formation and function.

Keywords: ABCA4; CLRN1; Exome sequencing; Inherited retinal dystrophy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP-Binding Cassette Transporters / genetics*
Adult
Child
Exome
Female
Humans
Male
Membrane Proteins / chemistry
Membrane Proteins / genetics*
Middle Aged
Mutation*
Pedigree
Phenotype
RNA Splicing
Retinal Dystrophies / genetics*
Retinal Dystrophies / pathology

Substances

ABCA4 protein, human
ATP-Binding Cassette Transporters
CLRN1 protein, human
Membrane Proteins