July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Panel-based next generation sequencing reveals extensive locus and allelic heterogeneity underlying inherited retinal degenerations in Mexican population
Author Affiliations & Notes
  • Juan Carlos Zenteno
    Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Cuauhtemoc, Mexico
    Biochemistry, Faculty of Medicine UNAM, Mexico
  • Leopoldo Garcia-Montaño
    Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Cuauhtemoc, Mexico
  • Marisa Cruz-Aguilar
    Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Cuauhtemoc, Mexico
  • Rodrigo Matsui-Serrano
    Retina, Institute of Ophthalmology "Conde de Valenciana", Mexico
  • Josue Ronquillo
    Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Cuauhtemoc, Mexico
  • Federico Graue-Wiechers
    Retina, Institute of Ophthalmology "Conde de Valenciana", Mexico
  • Luis Castul
    Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Cuauhtemoc, Mexico
  • Tatiana Urrea
    Retina, Institute of Ophthalmology "Conde de Valenciana", Mexico
  • Uises De Dios-Cuadras
    Retina, Institute of Ophthalmology "Conde de Valenciana", Mexico
  • Oscar Chacon-Camacho
    Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Cuauhtemoc, Mexico
  • Footnotes
    Commercial Relationships   Juan Zenteno, None; Leopoldo Garcia-Montaño, None; Marisa Cruz-Aguilar, None; Rodrigo Matsui-Serrano, None; Josue Ronquillo, None; Federico Graue-Wiechers, None; Luis Castul, None; Tatiana Urrea, None; Uises De Dios-Cuadras, None; Oscar Chacon-Camacho, None
  • Footnotes
    Support  CONACYT 1234413; Foundation Fighting Blindness Grant CD-GE-0816–0711-OICV
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2962. doi:
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      Juan Carlos Zenteno, Leopoldo Garcia-Montaño, Marisa Cruz-Aguilar, Rodrigo Matsui-Serrano, Josue Ronquillo, Federico Graue-Wiechers, Luis Castul, Tatiana Urrea, Uises De Dios-Cuadras, Oscar Chacon-Camacho; Panel-based next generation sequencing reveals extensive locus and allelic heterogeneity underlying inherited retinal degenerations in Mexican population. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2962.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Retinal dystrophies (RDs) are a group of inherited disorders arising from mutations in genes with a role in retinal development and function. RDs are the leading cause of inherited blindness worldwide and mutations in approximately 250 genes have been demonstrated to be causal for these disorders. The identification of the specific gene responsible in a particular RD case is critical for RD classification and prognosis. Recent application of next generation sequencing (NGS) techniques has greatly improved the molecular characterization of RD and analyses of additional RD cohorts are warranted as they will allow the expansion of the mutational spectrum linked to human RD.

Methods : The clinical diagnosis of RD was made by Retina specialists. NGS was performed using the ClearSeq Inherited Disease panel (Agilent Technologies) which includes 199 RD-related genes. Libraries were sequenced using the MiSeq Reagent kit v2 in a MiSeq platform (Illumina). Sequence data was read and mapped using the Burrows-Wheeler Aligner (BWA)-MEM algorithm and VarScan 2.3.6 was employed for variant calling. All candidate pathogenic variants were confirmed by Sanger sequencing in available family members

Results : A total of 138 probands with different forms of RDs, including 118 non-syndromic cases and 20 syndromic cases, were ascertained. Autosomal recessive retinitis pigmentosa (ARRP) was assumed in 33 probands, autosomal dominant RP (ADRP) in 15, X-linked RP (XLRP) in 3, and sporadic or simplex RP in 28 subjects, among other diagnosis. Causal pathogenic variants were identified in 96 cases, for a solving rate of 70% (96/138). A total of 111 distinct pathogenic variants, including 53 novel ones, were detected across 47 different RD genes. ABCA4 was the most commonly mutated gene in the group of solved cases (8%; 8/96), followed by CRB1 (7%; 7/96), and RPE65 (6%; (6/96). Twelve out of 16 (75%) simplex RP cases were reclassified as AR disease based on molecular findings.

Conclusions : This study represents the largest cohort of molecularly analyzed RD subjects from Mexico and Latin America and our results demonstrate a high genic and allelic heterogeneity underlying these disorders in our population. The molecular diagnostic yield varied among subtypes of RD, with cone-rod dystrophy and autosomal recessive RP being the commonest molecularly solved disorders.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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