A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma.

Joe Rainger,Anne Seawright,Julia Truch,Megan G Davey,Uk10K ,James Prendergast,Kathleen A Williamson,Dominic Kurian,Andrew C Gill,David R Fitzpatrick,Lynn Mcteir,Mihail Halachev,Dinesh C Soares,Ann Wheeler,Gabriele Gillessen‐Kaesbach,Veronica Heyningen

doi:10.1002/humu.23246

Joe Rainger, Anne Seawright + Show 14 more

Open Access

https://doi.org/10.1002/humu.23246

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Abstract

Ocular coloboma (OC) is a defect in optic fissure closure and is a common cause of severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole‐exome sequencing (WES) was used to analyze 12 trios (child affected with OC and both unaffected parents). This identified de novo mutations in 10 different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1, and LCP1. Proband‐only WES identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p.(Pro70Leu). Both individuals have normal neurodevelopment with no extra‐ocular signs of Baraitser–Winter syndrome. We found this mutant protein to be incapable of incorporation into F‐actin. The LCP1 and TWF1 variants each resulted in only minor disturbance of actin interactions, and no further plausibly causative variants were identified in these genes on resequencing 380 unrelated individuals with OC.

Highlights

We report Whole-exome sequencing (WES) on 12 trios, each comprising one affected individual with isolated Ocular coloboma (OC) and both unaffected parents
In proband COL5103597, a causative homozygous lossof-function mutation was identified in ADAMTS18, which has been reported separately (Chandra et al, 2014), and no de novo mutations (DNM) were identified in this trio
The DNM identified in ACTG1 (NM_001199954.1; MIM# 102560) in COL5231458 (family 12; c.209C>T (p.(Pro70Leu), RNA not analyzed)) represented a strong candidate because DNM in the ubiquitous cytoplasmic actins cause Baraitser– Winter syndrome (BWS) with OC as a prominent feature (MIM# 243310 and 614583) (Di Donato et al, 2014; Rivière et al, 2012)

Summary

Introduction

We report WES on 12 trios, each comprising one affected individual with isolated OC and both unaffected parents. Following review and Sanger sequence validation, 10 heterozygous de novo, ultrarare, plausibly disruptive variants were confirmed in 10 different genes from eight of the trios surveyed Review of the WES data from the remaining UK10K OC probands identified another individual, COL5103624 (family 1,135) with the identical DNM (c.209 C>T (p.(Pro70Leu), RNA not analyzed)).

Results

Conclusion