Identification of novel pathogenic variants and novel gene-phenotype correlations in Mexican subjects with microphthalmia and/or anophthalmia by next-generation sequencing. Issue 11 (November 2018)

• Record Type: Journal Article
• Authors: Matías-Pérez, Diana; García-Montaño, Leopoldo; Cruz-Aguilar, Marisa; García-Montalvo, Iván; Nava-Valdéz, Jessica; Barragán-Arevalo, Tania; Villanueva-Mendoza, Cristina; Villarroel, Camilo; Guadarrama-Vallejo, Clavel; Cruz, Rocío; Chacón-Camacho, Oscar; Zenteno, Juan
• Is Part Of: Journal of human genetics. Volume 63:Issue 11(2018)
• Page Start: 1169
• Page End: 1180
• Publication Date: 2018-11
• Subjects: Medical genetics -- Periodicals; Human genetics -- Periodicals; 616.042
• DOI: 10.1038/s10038-018-0504-1
• Languages: English
• ISSNs: 1434-5161

Abstract

Abstract Severe congenital eye malformations, particularly microphthalmia and anophthalmia, are one of the main causes of visual handicap worldwide. They can arise from multifactorial, chromosomal, or monogenic factors and can be associated with extensive clinical variability. Genetic analysis of individuals with these defects has allowed the recognition of dozens of genes whose mutations lead to disruption of normal ocular embryonic development. Recent application of next generation sequencing (NGS) techniques for genetic screening of patients with congenital eye defects has greatly improved the recognition of monogenic cases. In this study, we applied clinical exome NGS to a group of 14 Mexican patients (including 7 familial and 7 sporadic cases) with microphthalmia and/or anophthalmia. Causal or likely causal pathogenic variants were demonstrated in ~60% (8 out of 14 patients) individuals. Seven out of 8 different identified mutations occurred in well-known microphthalmia/anophthalmia genes(OTX2, VSX2, MFRP, VSX1 ) or in genes associated with syndromes that include ocular defects (CHD7, COL4A1 ) (including two instances ofCHD7 pathogenic variants). A single pathogenic variant was identified inPIEZO2, a gene that was not previously associated with isolated ocular defects. NGS efficiently identified the genetic etiology of microphthalmia/anophthalmia in ~60% of cases included in this cohort, the first from Mexican origin analyzed to date. The molecular defects identified through clinical exome sequencing in this study expands the phenotypic spectra ofCHD7 -associated disorders and implicatePIEZO2 as a candidate gene for major eye developmental defects.