Identification of a novel nonsense mutation p.Tyr1957Ter of CACNA1A in a Chinese family with episodic ataxia 2

Abstract

Type 2 episodic ataxia (EA2) is the most common subtype among a group of rare hereditary syndromes characterized by recurrent attacks of ataxia. More than 60 mutations and several gene rearrangements due to large deletions in CACNA1A gene have been reported so far for the cause of EA2. Because CACNA1A gene is a large gene containing 47 exons and there is no hot spot mutation, direct sequencing will be a challenge in clinical genetic testing. In this study, we used next generation sequencing technology to identify a novel nonsense mutation of CACNA1A (p.Tyr1957Ter, NP_001120693.1) resulting in truncated protein without 305 amino acids in the c-terminus. Sanger sequencing confirmed the heterozygous mutation of CACNA1A in a Chinese family with 11 affected individuals. Affected individuals experienced recurrent attacks with or without nystagmus, dysarthria, seizure, myokymia, dystonia, weakness, blurred vision, visual field defects, diplopia, migraine, dizziness, nausea and vomiting, sweating and abdominal pain. This is the first report of EA2 in a Chinese family that carries a novel mutation in CACNA1A gene and had abdominal pain as a novel phenotype associated with EA2.

Figure 1. Pedigree of four generation family with EA2.

Generations are shown as I to IV. Individuals affected with episodic ataxia are indicated by a black filled circle or square for females or males. Numbers (1–12) were assigned to individuals who agreed to take blood samples. The proband (III-7) is indicated by an array. DNA samples went to next generation sequencing were labeled with Asterisk (*).

Figure 2. Identification of novel premature mutation (p.Tyr1957Ter) in the c-tail of CACNA1A in a Chinese EA2 family.

A. Schematic of the bioinformatics analysis pipeline of data from next generation sequencing to identify nonsense mutation (p.Tyr1957Ter) in CACNA1A. SNP, single nucleotide polymorphism, InDels, insertions or deletions, BWA, Burrows-Wheeler Alignment Tool, SNV, single nucleotide variants. B. Confirmation of a heterozygous mutation in CACNA1A (c.6107C>A, NM_001127221.1, p.Tyr1957Ter, NP_001120693.1) by Sanger sequencing in the proband. C. A heterozygous C/A change at nucleotide 6107 in the affected individual D. C/C sequence at nucleotide 6107 in grandfather (I-1).