Submission Details

FBLN5 was first reported in relation to autosomal dominant demyelinating hereditary motor and sensory neuropathy in 2011 (PMID: 21576112). FBLN5 is a member of the fibulin family of proteins which are extracellular matrix proteins characterized by tandem arrays of EGF-like domains and a C-terminal fibulin-type module. This gene consists of 11 exons that are differentially combined in three major transcripts.

FBLN5 is also reported in association with autosomal dominant and recessive cutis laxa, a connective tissue disorder, and autosomal dominant age-related macular degeneration. Available data and input from our expert panel indicates these phenotypes should be split: there is phenotypic variability, differences in inheritance pattern (autosomal recessive, autosomal dominant, and autosomal dominant with age-related penetrance), and differences in molecular mechanism (cutis laxa variants are biallelic loss of function or heterozygous dominant-negative, which is different from the variants associated with macular degeneration and neuropathy). However, there are cases with overlapping features suggesting a possible phenotypic spectrum. For example, many of the individuals referenced in this curation have neuropathy with variable connective tissue features (hyperelastic skin, hypermobility) and age-related macular degeneration. There is at least one variant that has been reported in both individuals with neuropathy and in individuals with isolated age-related macular dystrophy (p.G267S, PMID: 21576112).

In this curation, we scored evidence for 6 missense variants in over 15 families (some with shared haplotype)- p.G90S, p.V126M, p.G267S, p.D329V, p.R331H, and p.R373C (PMIDs: 21576112, 23328402, 28332470, 31945625, 32757322). A single variant (p.R373C) arose in multiple unique haplotypes and is considered a hotspot variant. Age of onset and phenotype varied between and within families but generally consisted of adult-onset progressive peripheral sensorimotor neuropathy with foot deformities, upper and lower limb sensory disturbances, and impaired gait with or without hypo/areflexia, muscle weakness, hyperelastic skin, hypermobility, and age-related macular degeneration. The mechanism of pathogenicity appears to be loss-of-function. Genetic evidence score totaled 3.1. Of note, there are additional families and variants not included in this curation as insufficient clinical data was reported (e.g. lack of electromyography to confirm neuropathy).

A single publication reports extensive experimental evidence including expression data, non-patient cell functional alteration, non-human model organism, and rescue in a non-human model organism (PMID: 33107705). The non-human (zebrafish) model showed that lack of FBLN5 leads to myelination defects which can be rescued to normal myelination levels with exogenous overexpression of FBLN5. Experimental evidence score is 5. The total score is 8.1. In summary, FBLN5 is moderately associated with autosomal dominant demyelinating hereditary motor and sensory neuropathy.