A Novel KCND3 Variant in a Korean Family With SCA19.

Dear Editor,

Spinocerebellar ataxias (SCAs) are autosomal dominant (AD) hereditary diseases with 48 subtypes identified to date.1 Genetically, SCAs are divided into trinucleotide repeat (TNR) expansions and nonrepeat mutations. Polyglutamine repeat mutations are a major cause of SCAs, and missense mutations, deletions, and duplications also lead to SCAs.12 Since SCAs present with heterogeneous clinical features that overlap different subtypes,2 genetic tests are useful for a definitive diagnosis.

SCA19 (MIM 607346) is an adult-onset cerebellar ataxia due to a missense mutation in KCND3. We identified a Korean family with SCA19 harboring the novel c.1054A>G (p. T352A) variant in KCND3 (NM_004980.5).

A 44-year-old male complained of progressive gait disturbance that began in his early twenties. He had never suffered from any perinatal events, developmental delays, or seizures. He presented with saccadic pursuit, hypermetric saccades, cerebellar dysarthria, limb ataxia, and hyperreflexia (Supplementary Video 1 in the online-only Data Supplement). His score on the International Cooperative Ataxia Rating Scale was 43, with the following subscores: static, 17; limb coordination, 19; dysarthria, 4; and oculomotor, 3. His modified Barthel Index score was 81, indicating that he required assistance to ensure safe walking (Supplementary Table 1 in the online-only Data Supplement). Brain magnetic resonance imaging showed diffuse cerebellar atrophy (Fig. 1A).

Fig. 1

Brain magnetic resonance imaging (MRI) and the family pedigree of the proband, and electropherograms of the proband and family members. A: Brain MRI of the proband revealed diffuse cerebellar atrophy. B: The family pedigree of the 44-year-old male (arrow) showed an autosomal dominant inheritance pattern. C: Electropherograms illustrating the c.1054A>G (p.T352A) missense mutation in KCND3 that was detected as a heterozygous peak (arrow) in the proband, his mother, and his symptomatic sisters.

The proband’s family history suggested an AD trait, since his mother, two older sisters, grandfather, and two uncles on his mother’s side were also affected (Fig. 1B). Dysarthria, unsteadiness, or hand incoordination appeared in the third or early in the fourth decade of life, and the symptoms progressed slowly without affecting daily activities (Supplementary Table 1 in the online-only Data Supplement).

The patient’s mother had previously tested negative in an SCA panel test that included SCA1, SCA2, SCA3, SCA6, SCA7, and SCA8. We therefore conducted next-generation sequencing on the proband, which identified the c.1054A>G (p.T352A) variant in KCND3 (Fig. 1C). This variant had not been reported in the following databases: the Genome Aggregation Database (https://gnomad.broadinstitute.org), the Korean Reference Genome Database (https://coda.nih.go.kr/coda/frt/index.do), PubMed (https://pubmed.ncbi.nlm.nih.gov), or the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php).

The variant was predicted to be deleterious by in silico analysis tools: SIFT (https://sift.bii.a-star.edu.sg), PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/), and MutationTaster (https://www.mutationtaster.org). Sanger sequencing confirmed that this variant was present in the mother and the symptomatic sisters (Fig. 1C), but absent in the asymptomatic sister. According to the American College of Medical Genetics guideline, the variant was classified as likely pathogenic based on the following criteria: PM1, PM2, PM5, PP2, and PP3.

KCND3 mutations may result in both loss and gain of function, as seen in cases of SCA19 and Brugada syndrome 9, respectively.3 KCND3 encodes Kv4.3, an alpha subunit of the Shal family of the A-type voltage-gated potassium channel.3 Approximately 70 cases of KCND3-related neurological disorders have been reported, with diverse onset ages and additional phenotypes including parkinsonism, cognitive decline, and epilepsy (Supplementary Table 2 in the online-only Data Supplement).4 The clinical heterogeneity may be associated with pathological evidence variously involving the cerebellar Purkinje cell layer, substantia nigra pars compacta, nucleus raphe interpositus, and cerebral cortex.5

As described in Supplementary Table 2 (in the online-only Data Supplement), we were unable to find links between specific nucleotide or amino acid alterations and clinical features. Patients with the p.T352P variant, which is a missense mutation in the same extracellular loop of KCND3 as that of our family case, present with complex phenotypes,6 and those with the p.T377M variant demonstrate diverse clinical characteristics.7 Even within our family case, a genotype–phenotype association could not be determined; the proband had additional pyramidal tract involvement while the other affected family members showed pure cerebellar ataxia.

In summary, we report a novel variant in KCND3 in a Korean family with SCA19. When a patient exhibits cerebellar ataxia with apparent AD inheritance, both TNR and non-TNR SCAs should be considered in the differential diagnosis.