Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Abstract

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

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

“…New genetic variants were detected in CFH , CFI , C3 and C9 , in addition to other genes ( FBN2 and HMCN1 ). Although rare variants segregated with AMD in some of these families (Pras et al, 2015, Ratnapriya et al, 2014, Yu et al, 2014), several variants did not perfectly segregate with the disease, but were enriched in cases compared to control individuals (Geerlings et al, 2016, Hoffman et al, 2014, Saksens et al, 2016). This is in line with the complex etiology of AMD, to which both common and rare genetic variants, and also environmental factors contribute.…”

“…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 ).…”

Genomic approaches for understanding the genetics of complex disease

“…It is likely that some combination of those different potential mechanisms accounts for the underlying architecture of complex diseases and traits as common, low frequency, and rare variants have all now been shown to be associated with complex diseases and traits Morrison et al 2013;Ratnapriya et al 2014;Surakka et al 2015).…”

Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration

“…Recent studies where whole exome/genome sequencing strategies were used have resulted in the successful identification of several rare variants, including the p.K155Q variant in C3 ,28 p.E1144 K variant in FBN2 29 and three other CFH variants: p.P503A,30 p.R53C and p.D90G 31. Another, yet to be implicated, benefit of this application relates to the comprehensive genetic data provided on multiple common and rare variants collectively, which could shed better insights into genotype–phenotype correlations.…”