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Submicroscopic deletions at 13q32.1 cause congenital microcoria.

ABSTRACT: Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR.

SUBMITTER: Fares-Taie L

PROVIDER: S-EPMC4385178 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Submicroscopic deletions at 13q32.1 cause congenital microcoria.

Fares-Taie Lucas L Gerber Sylvie S Tawara Akihiko A Ramirez-Miranda Arturo A Douet Jean-Yves JY Verdin Hannah H Guilloux Antoine A Zenteno Juan C JC Kondo Hiroyuki H Moisset Hugo H Passet Bruno B Yamamoto Ken K Iwai Masaru M Tanaka Toshihiro T Nakamura Yusuke Y Kimura Wataru W Bole-Feysot Christine C Vilotte Marthe M Odent Sylvie S Vilotte Jean-Luc JL Munnich Arnold A Regnier Alain A Chassaing Nicolas N De Baere Elfride E Raymond-Letron Isabelle I Kaplan Josseline J Calvas Patrick P Roche Olivier O Rozet Jean-Michel JM

American journal of human genetics 20150312 4

Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied fr ...[more]

PMID: 25772937

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Project description:The application of genome sequencing in patients with intellectual disability and congenital anomalies (ID/CA) typically identifies causative mutations only in a minority of cases. We hypothesized that some cases of ID/CA are caused by epigenetic aberrations that dysregulate normal genome function, and that these would be missed by conventional sequencing approaches. We performed Illumina 450k DNA methylation profiling in ~500 individuals with ID/CA, who were negative for causative mutations by microarray, exome- and/or whole genome sequencing. We screened patient methylation profiles for epimutations absent in ~1,500 controls, and validated these by bisulfite sequencing, revealing that epimutations represent large methylation changes specifically on one allele. Parental studies show that approximately half represent de novo events, a rate significantly higher than that seen in controls. We identified seven recurrent events, two of which (FMR1, MEG3) have known disease associations, validating our method for detecting pathogenic epimutations. From large-scale sequencing, population and expression studies we conclude that epimutations are: (i) Frequently associated with extreme outlier and mono-allelic gene expression, with an impact comparable to loss-of-function mutations; (ii) Generally conserved across multiple tissues within an individual, validating the use of blood DNA to study ID/CA; (iii) Can occur secondary to cis-linked regulatory mutations, providing a rationale for interpreting non-coding genetic variants; (iv) Occur sporadically with a remarkably high de novo rate, and (v) Exhibit non-Mendelian inheritance, likely being reset between generations by epigenetic reprogramming during embryogenesis. We conclude that epimutations underlie 5-10% of patients with ID/CA who are refractory to conventional mutation screening, and propose that epigenome profiling represents a promising method for the study of human disease that complements sequence-based approaches.

Dataset Information

Submicroscopic deletions at 13q32.1 cause congenital microcoria.

Publications

Submicroscopic deletions at 13q32.1 cause congenital microcoria.

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