Digenic FLNA and UCHL1 variants resulting in a complex phenotype

Aim X‐linked variants in Filamin A (FLNA) are associated with the Ehlers‐Danlos‐syndrome‐variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C‐terminal hydrolase L1 (UCHL1) are associated with a late‐onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole‐gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype. Methods A 67‐year‐old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4‐year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss. Results Neurophysiology including Somatosensory‐evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene. Conclusions To the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants.