1. Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
- Author
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Julien Derolez, Hannah Verdin, Carmen Ayuso, Frauke Coppieters, Marta Corton, Frank Peelman, Marianthi Karali, Francesca Simonelli, Thalia Van Laethem, Kamron N. Khan, Julie De Zaeytijd, Jenneke van den Ende, Belen Jimenez, Sandro Banfi, Manir Ali, Francesco Testa, Elfride De Baere, Claire E. L. Smith, Martin McKibbin, Annalaura Torella, Timothy J. Cherry, Bart P. Leroy, Carmel Toomes, Chris F. Inglehearn, Toon Rosseel, Kristof Van Schil, Stijn Van De Sompele, Van de Sompele, Stijn, Smith, Claire, Karali, Marianthi, Corton, Marta, Van Schil, Kristof, Peelman, Frank, Cherry, Timothy, Rosseel, Toon, Verdin, Hannah, Derolez, Julien, Van Laethem, Thalia, Khan, Kamron N., Mckibbin, Martin, Toomes, Carmel, Ali, Manir, Torella, Annalaura, Testa, Francesco, Jimenez, Belen, Simonelli, Francesca, De Zaeytijd, Julie, Van den Ende, Jenneke, Leroy, Bart P., Coppieters, Frauke, Ayuso, Carmen, Inglehearn, Chris F., Banfi, Sandro, and De Baere, Elfride
- Subjects
0301 basic medicine ,EXPRESSION ,CRX ,PROTEIN ,Disease ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,retinitis pigmentosa ,Retinitis pigmentosa ,medicine ,Medicine and Health Sciences ,Genetics (clinical) ,Loss function ,Sequence (medicine) ,HOMEOBOX GENE [novel ARRP gene KeyWords Plus] ,Genetics ,MUTATIONS ,novel ARRP gene ,Biology and Life Sciences ,Retinal ,RAX2 ,medicine.disease ,030104 developmental biology ,chemistry ,loss of function ,homeobox-containing transcription factor ,Human medicine ,NRL - Abstract
Purpose: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. Methods: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. Results: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. Conclusion: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases. Purpose: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. Methods: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. Results: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. Conclusion: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.
- Published
- 2019