Our research focusses on the genetic basis of FEVR in sporadic and familial cases by identifying and functionally characterizing mutations in known genes (see below) as well as in novel genes, not yet implicated in FEVR and similar diseases. For this purpose, we use next generation sequencing of retinal gene panels (NGS panels) and whole exome sequencing (WES).
Symptoms and clinical features of FEVR
Familial exudative vitreoretinopathy (FEVR) is characterized by an abnormal vascular development in the peripheral retina of the human eye. Visual problems in patients result from secondary complications caused by retinal ischemia. The avascular retina is present from birth and may progress with long-term complications in adulthood. Expressivity may be asymmetric and highly variable, ranging from mild or asymptomatic to severe (e.g., registered as blind) within the same family. This intrafamilial variability of the disease symptoms might be attributed to genetic and environmental modifiers. The clinical diagnosis is based on fundus fluorescein angiography. FEVR is of particular interest as it involves angiogenic processes.
FEVR can appear as part of a complex phenotype (syndromic FEVR), e.g. in osteoporosis pseudoglioma syndrome (OPPG) or Norrie disease (ND), with an autosomal or X-linked recessive mode of inheritance, respectively. Non-syndromic forms show no extraocular features. The mode of inheritance is autosomal dominant or recessive or X-linked recessive. Rarely, mutations in LRP5 are dominant and TSPAN12 mutations recessive.
Genetic heterogeneity of FEVR
Mutations in seven genes are known to be associated with FEVR: FZD4, encoding the protein frizzled-4; LRP5, encoding low-density lipoprotein receptor-related protein 5; TSPAN12, encoding tetraspanin-12; and NDP, coding for Norrin. More recently, mutations in ATOH7, KIF11 and ZNF408 were also associated with FEVR. The modes of inheritance of mutations are autosomal dominant (FZD4, KIF11, LRP5, TSPAN12 and ZNF408), autosomal recessive (ATOH7, LRP5), or X-linked recessive (NDP).
Frequencies of FEVR-associated mutations (n=202) in 7 genes (ATOH7, FZD4, KIF11, LRP5, NDP, TSPAN12 and ZNF408). Mutations in FZD4 are dominant and account for 40% of the cases with FEVR. The second most frequently mutated gene is LRP5 (28%). These mutations are mostly recessive but some dominant were also described. Mutations in TSPAN12 account for 14% of the cases, and in KIF11, NDP, ZNF408 and ATOH7 for 18% (percentage based on 202 FEVR-associated mutations from HGMD as of February 2017). TSPAN12 mutations are mostly dominant, with only few exceptions, where a recessive mode of transmission was described. NDP mutations are X-linked recessive and the majority of them leads to Norrie disease, which is much more severe compared to FEVR. Currently, mutations in these seven genes can explain only 50% of the cases with FEVR. Mutations in additional genes are expected to cause the disease in so far unexplained or undiagnosed patients. NDP encodes Norrin, a ligand of the receptor and co-receptors FZD4, LRP5 and TSPAN12. This ligand-receptor complex is known to trigger retinal angiogenesis. This mechanism is highly relevant not only to many other human diseases with abnormal vascular development but also for therapeutic intervention.
Table: Genes and numbers of mutations associated with FEVR.
|Gene||Number of Exons||Protein||Number of Amino Acids||Number of Mutations*|
*Numbers from Human Gene Mutation Database (HGMD), February 2017
1Low-density lipoprotein receptor-related protein 5
2Kinesin family member 11
3Zinc finger protein 408
4Atonal homolog 7
5RCC1 and BTB domain containing protein 1
Clinical variability of symptoms
The severity of FEVR varies tremendously and is unpredictable, even within the same family and even between the eyes of the same patient. There are overlapping clinical features or symptoms due to mutations in the four genes.
Mutations in NDP may give rise to blindness, deafness and intellectual disability and thus affect ocular, auditory and central nervous tissues. In contrast, mutations in FZD4 and TSPAN12 do exclusively result in ocular symptoms while LRP5 mutations also may affect bones and brain. Also, the mode of inheritance can be variable. FZD4 and TSPAN12 carry dominant mutations in the vast majority of cases, while LRP5 mutations are usually autosomal recessive or dominant and NDP mutations X-linked recessive. In the latter case, only males are affected and female carriers have no symptoms, with only very few exceptions.