Exome sequencing of choreoacanthocytosis reveals novel mutations in VPS13A and co-mutation in modifier gene(s)

Abstract

Choreoacanthocytosis, one of the forms of neuroacanthocytosis, is caused by mutations in vacuolar protein sorting-associated protein A (VPS13A), and is often misdiagnosed with other form of neuroacanthocytosis with discrete genetic defects. The phenotypic variations among the patients with VPS13A mutations significantly obfuscates the understanding of the disease and treatment strategies. In this study, two unrelated cases were identified, exhibiting the core phenotype of neuroacanthocytosis but with considerable clinical heterogeneity. Case 1 presented with an additional Parkinsonism phenotype, whereas seizures were evident in case 2. To decipher the genetic basis, whole exome sequencing followed by validation with Sanger sequencing was performed. A known homozygous pathogenic nonsense mutation (c.799C > T; p.R267X) in exon 11 of the VPS13A gene was identified in case 1 that resulted in a truncated protein. A novel missense mutation (c.9263T > G; p.M3088R) in exon 69 of VPS13A identified in case 2 was predicted as pathogenic. In silico analysis of the p.M3088R mutation at the C-terminus of VPS13A suggests a loss of interaction with TOMM40 and may disrupt mitochondrial localization. We also observed an increase in mitochondrial DNA copy numbers in case 2. Mutation analysis revealed benign heterozygous variants in interacting partners of VPS13A such as VAPA in case 1. Our study confirmed the cases as ChAc and identified the novel homozygous variant of VPS13A (c.9263T > G; p.M3088R) within the mutation spectrum of VPS13A-associated ChAc. Furthermore, mutations in VPS13A and co-mutations in its potential interacting partner(s) might contribute to the diverse clinical manifestations of ChAc, which requires further study.

Case report: Misdiagnosed orolingual dyskinesia as a consequence of seizures in a chorea-acanthocytosis patient with a novel VPS13A variation from a family with consanguineous marriage

“…In the ChAc cases that presented epilepsy as the first and prominent symptom, except for the homozygous frameshift mutation of c.2061dup in our case, nonsense mutations caused by c.8282C > G or c.4326 T > A, frameshift mutation caused by c.2343del or deletion of exons 70–73 and missense mutation caused by c.9263 T > G in exon 69 of VPS13A were reported, which all result in loss-of-function of the encoded protein around the C-terminus ( 6 , 10 , 12 , 18 , 19 ). As a gene spanning 240 kb and consisting of 73 exons, the C-terminus of VPS13A (amino acids 2,615–3,174) has been clearly demonstrated to be important for mitochondrial localization ( 19 , 20 ). Whether the occurrence of seizures in ChAc is the consequence of disruption of mitochondrial localization needs further exploration.…”