Whole Exome Sequencing in Patients with the Cuticular Drusen Subtype of Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly people worldwide. Cuticular drusen (CD) is a clinical subtype of AMD, which typically displays an earlier age at onset, and has a strong genetic component. Genetic studies support a role for rare sequence variants in CD susceptibility, and rare sequence variants in the CFH gene have been identified in 8.8% of CD cases. To further explore the role of rare variants in CD, we performed whole exome sequencing (WES) in 14 affected members of six families and 12 sporadic cases with CD. We detected rare sequence variants in CFH and FBLN5, which previously were shown to harbor rare variants in patients with CD. In addition, we detected heterozygous rare sequence variants in several genes encoding components of the extracellular matrix (ECM), including FBLN1, FBLN3/EFEMP1, FBLN5, FBLN6/HMCN1, FBN2, and COL15A1. Two rare pathogenic variants were identified in the COL15A1 gene: one in a sporadic case and another was found to segregate in a family with six affected individuals with CD. In addition, two rare pathogenic variants were identified in the FGL1 gene in three unrelated CD cases. These findings suggest that alterations in the ECM and in the coagulation pathway may play a role in the pathogenesis of CD. The identified candidate genes require further analyses in larger cohorts to confirm their role in the CD subtype of AMD. No evidence was found of rare sequence variants in a single gene that segregate with CD in the six families, suggesting that the disease is genetically heterogeneous.

Eculizumab cessation in atypical hemolytic uremic syndrome

“…For example, patient 4 has been in clinical remission for 2.6 years, with continued evidence of complement activation in vitro, and harbors homozygous deletion of CFHR3-CFHR1 associated with increased hemolysis in vitro 19 and a CFH mutation (Gln950His) previously observed in aHUS 22 and predicted to be functionally damaging. 23 We show that eculizumab can be safely discontinued in select adult patients with aHUS, despite continued complement activation. Our observed relapse rate (20%) compares favorably to the 31% reported in 2 series, 10,24 and 2 of 3 relapses occurred in the setting of nonadherence.…”

The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment

“…To date only few rare variants have been consistently replicated across multiple cohorts (Fritsche et al, 2016, Helgason et al, 2013, Raychaudhuri et al, 2011, Seddon et al, 2013, van de Ven et al, 2013, Zhan et al, 2013). While some rare variants are present relatively abundantly in one population, they are virtually absent in other populations, for example Arg1210Cys in CFH (Duvvari et al, 2015, Miyake et al, 2015, Raychaudhuri et al, 2011, Zhan et al, 2013) and Gly119Arg in CFI (Alexander et al, 2014, Cheng et al, 2015, Kavanagh et al, 2015, van de Ven et al, 2013). …”

“…Since WES and WGS are expensive to perform in large cohorts, approaches can be used to enrich for rare variants, for example by analyzing large AMD families. Recent studies in AMD using WES and WGS have successfully identified novel genetic variants in AMD using a case-control cohort (Helgason et al, 2013) or by analyzing multiple affected individuals of large AMD families (Duvvari et al, 2016, Geerlings et al, 2016, Hoffman et al, 2014, Pras et al, 2015, Ratnapriya et al, 2014, Saksens et al, 2016, Yu et al, 2014). New genetic variants were detected in CFH , CFI , C3 and C9 , in addition to other genes ( FBN2 and HMCN1 ).…”

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity

“…[23,10] It is interesting that two top candidate genes identified in this study, ADCK4 and COL15A1 , are also associated with retinal disorders. [24,25] However, the possible association between different types of ocular abnormalities and TAA severity remains unclear. Detailed ocular phenotyping in heritable TAA is indicated and may identify clinical features useful for TAA risk prediction.…”