A Novel de novo KIF1A Mutation in a Patient with Ataxia, Intellectual Disability and Mild Foot Deformity

Abstract

Early-onset ataxias are often difficult to diagnose due to the genetic and phenotypic heterogeneity of patients. Whole exome sequencing (WES) is a powerful method for determining causative mutations of early-onset ataxias. We report a case in which a novel de novo KIF1A mutation was identified in a patient with ataxia, intellectual disability and mild foot deformity.A patient presented with sporadic forms of ataxia with mild foot deformity, intellectual disability, peripheral neuropathy, pyramidal signs, and orthostatic hypotension. WES was used to identify a novel de novo mutation in KIF1A, a known causative gene of neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment syndrome (NESCAVS).We report a novel phenotype of NESCAVS that is associated with a novel de novo missense mutation in KIF1A, which provides valuable information for the diagnosis of NESCAVS even in the era of WES. Early rehabilitation of patients with NESCAVS may prevent symptom worsening and improve the disease course.

Keywords: Ataxia; Foot deformity; Intellectual disability; KIF1A; Whole-exome sequencing.

Fig. 1

Patient symptoms and genetic features. The front (a) and lateral (b) views of the patient’s feet show that they are short and flat feet, with disproportionally narrow width in the anterior portion. The front view of the plain radiographs of the patient’s feet (c) showed hypoplastic calcaneus bones and arches. Axial (d) and sagittal (e) views of fluid-attenuated inverted recovery (FLAIR) MRI images of the brain revealing severe cerebellar atrophy and moderate dilatation of the fourth ventricle are shown. Whole exome sequencing analysis (WES) identified a novel heterozygous mutation in the KIF1A gene [c.799G > C (p.E267Q)]. Electropherograms of direct nucleotide sequence analyses are shown (f) on the left side of corresponding individuals. The arrow indicates the index patient and arrowheads indicate a mutation site. The mutation was not identified in the patient’s parents. Therefore, it was considered a de novo mutation based on the consistent parent-descendant relationship supported by the genotyping of three surrounding microsatellite markers (GATA178G09, AGAT021 and 2QTEL47)