Gene Variant Spectrum in Probands With Familial Exudative Vitreoretinopathy Using an Expanded Panel

Abstract

Purpose: To investigate the gene variant spectrum in patients with familial exudative vitreoretinopathy (FEVR).

Methods: Probands clinically diagnosed with FEVR and their relatives were enrolled and clinical information and DNA collected. An expanded FEVR panel was used, including six recognized FEVR genes (FZD4, NDP, LRP5, TSPAN12, ZNF408, and CTNNB1) and 19 genes previously associated with ocular features overlapping FEVR (FEVR-associated genes). Variants identified using targeted next-generation sequencing and/or Sanger sequencing were analyzed and classified using the American College of Medical Genetics and Clinical Genome Resource Sequence Variant Interpretation (ClinGen SVI) working group recommendations to detect disease-causing variants (DCVs).

Results: Analyses of data from a cohort of 94 probands provided a molecular diagnosis for 39 (41.5%) probands: 34 (87.2%) had a single DCV, whereas 5 (12.8%) harbored more than 1 DCV. Of 41 total DCVs in solved probands, 33 (80.5%) were in 4 of the 6 recognized genes, LRP5, FZD4, TSPAN12, and NDP, whereas 8 were found in FEVR-associated genes, 6 in KIF11, and 2 (LAMA1 and DOCK6) each in association with a KIF11 DCV. Reanalyzing variants using the latest criteria impacted the variant classification in five probands (5.3%), changing variants that were once deemed likely pathogenic to variants of uncertain significance.

Conclusions: The expanded FEVR gene panel detected DCVs in nearly one-half of our cohort. Including the criteria used in classification will improve transparency of variant calls as more data become available. Four FEVR genes account for most cases, and the role of rare FEVR genes and candidate genes requires further study.

Figure 1.

Isolated and syndromic FEVR: genetic causes and inheritance. Genes in bold text designate the six FEVR genes, to differentiate them from genes that may cause a phenotype overlapping that of FEVR, that is, FEVR-associated genes. Owing to variable expressivity or effect of the variant on protein function, among other, 6 of the 25 genes have been reported with or without extraocular manifestations, highlighting the possibility that some cases diagnosed as FEVR may be caused by one of those six genes. NDP has been reported as a cause of FEVR or Norrie disease, including ocular manifestations in carriers that range from a forme fruste to severe disease (e.g., childhood onset retinal detachment), although typically less severe than what is seen in affected males. The predominant mode of inheritance of FEVR caused by LRP5 and FZD4 is autosomal dominant (AD), but AR forms, including syndromic forms, have been reported.

Figure 2.

Diagnostic flow diagram. Summary of diagnostic work up and genetic test results.

Figure 3.

(A) Distribution and location of missense variants among A. LRP5. All of the missense DCVs identified, both known and new, are in the extracellular domain of the LRP5 protein and are each contained in a b-propeller domain, with these domains being important during FZD4 receptor complex formation and intracellular signal generation. (B) FZD4. Of the four previously reported missense DCVs, three are located in the N-terminal cysteine-rich domain (p.Met105Val, p.Ile114Thr, p.Met157Lys), with two of the newly identified FZD4 DCVs also located in the N-terminal domain (p.Leu66Gln, p.Cys106Gly). All of these variants are in the Norrin-binding domain of the FZD4 protein. Disruptions in Norrin-FZD4 binding significantly decrease the activation of the Norrin/Frizzled4 signaling pathway and cause FEVR. The remaining missense DCVs present in the C-terminus was previously reported and is required for glycosylation of the FZD4 protein. (C) KIF11. (D) TSPAN12. (E) NDP. (F) DOCK6. (G) LAMA1.

Figure 3.

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Figure 3.

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