Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden and lower antigenic levels in familial AMD

Abstract

The genetic architecture of age-related macular degeneration (AMD) involves numerous genetic variants, both common and rare, in the coding region of complement factor H (CFH). While these variants explain high disease burden in some families, they fail to explain the pathology in all. We selected families whose AMD was unexplained by known variants and performed whole exome sequencing to probe for other rare, highly penetrant variants. We identified four rare loss-of-function variants in CFH associated with AMD. Missense variant CFH 1:196646753 (C192F) segregated perfectly within a family characterized by advanced AMD and drusen temporal to the macula. Two families, each comprising a pair of affected siblings with extensive extramacular drusen, carried essential splice site variant CFH 1:196648924 (IVS6+1G>A) or missense variant rs139360826 (R175P). In a fourth family, missense variant rs121913058 (R127H) was associated with AMD. Most carriers had early onset bilateral advanced AMD and extramacular drusen. Carriers tended to have low serum Factor H levels, especially carriers of the splice variant. One missense variant (R127H) has been previously shown not to be secreted. The two other missense variants were produced recombinantly: compared to wild type, one (R175P) had no functional activity and the other (C192F) had decreased secretion.

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

“…Splice site variant CFH c.790 + 1G > A and coding variants CFH Arg53Cys, Asp90Gly, Arg127His, Arg175Pro, Arg175Gln, Cys192Phe, and Ser193Leu were identified by WES of AMD families in which known genetic risk factors could not explain the high burden of disease (Geerlings et al, 2016, Wagner et al, 2016, Yu et al, 2014). Variant CFH Pro503Ala was identified using WES in an Amish family after exclusion of the other main risk variants for AMD, and was significantly associated with AMD in an Amish AMD case-control cohort (Hoffman et al, 2014) (Table 2).…”

“…Later, variants c.790 + 1G > A, Arg127His, Arg175Pro and Cys192Phe were analyzed for levels of serum concentration, and all variants, except Arg127His, had reduced FH serum levels compared to a control group. The coding variants all shown impaired protein secretion (Albuquerque et al, 2012, Wagner et al, 2016). …”

Genotype‐phenotype correlations of low‐frequency variants in the complement system in renal disease and age‐related macular degeneration

“…Previous studies in densely affected AMD families detected several AMD-specific variants in the first 4 SCR domains of FH (eg, p.Asp90Glu, p.Arg175Pro, p.Arg175Gln, p.Cys192Phe, and p.Ser193Leu), underscoring the importance of these domains in the disease pathogenesis of AMD. 12,22,33 Previously, more than 60% of the aHUS-associated FH mutations were reported in the Cterminal domains. 21 Variants in this region interfere with heparin, C3b, and C3d binding, and result in reduced cell-surface interaction.…”

Complement Dysregulation and Disease: Insights from Contemporary Genetics

“…A number of genetic alterations are associated with increased risk of developing AMD, and many reside in genes encoding the complement cascade (32–37). These variants span the allelic spectrum of disease from common variants (exhibiting relatively low risk) to rare variants with complete penetrance.…”