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Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease

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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.
Keywords
RAX2, homeobox-containing transcription factor, loss of function, novel ARRP gene, retinitis pigmentosa

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Please use this url to cite or link to this publication:

Chicago
Van De Sompele, Stijn, Claire Smith, Marianthi Karali, Marta Corton, Kristof Van Schil, Frank Peelman, Timothy Cherry, et al. 2019. “Biallelic Sequence and Structural Variants in RAX2 Are a Novel Cause for Autosomal Recessive Inherited Retinal Disease.” Genet. Med.
APA
Van De Sompele, S., Smith, C., Karali, M., Corton, M., Van Schil, K., Peelman, F., Cherry, T., et al. (2019). Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease. Genet. Med.
Vancouver
1.
Van De Sompele S, Smith C, Karali M, Corton M, Van Schil K, Peelman F, et al. Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease. Genet. Med. 2019;
MLA
Van De Sompele, Stijn et al. “Biallelic Sequence and Structural Variants in RAX2 Are a Novel Cause for Autosomal Recessive Inherited Retinal Disease.” Genet. Med. (2019): n. pag. Print.
@article{8586361,
  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.},
  author       = {Van De Sompele, Stijn and Smith, Claire and Karali, Marianthi and Corton, Marta and Van Schil, Kristof and Peelman, Frank and Cherry, Timothy and Rosseel, Toon and Verdin, Hannah and Derolez, Julien and Van Laethem, Thalia and N. Khan, Kamron and McKibbin, Martin and Toomes, Carmel and Ali, Manir and Torella, Annalaura and Testa, Francesco and Simonelli, Francesca and De Zaeytijd, Julie and Van den Ende, Jenneke and Leroy, Bart and Coppieters, Frauke and Ayuso, Carmen and Inglehearn, Chris F and Banfi, Sandro and De Baere, Elfride},
  issn         = {1098-3600},
  journal      = {Genet. Med.},
  language     = {eng},
  title        = {Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease},
  url          = {http://dx.doi.org/10.1038/s41436-018-0345-5},
  year         = {2019},
}

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