Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity.

Utilizing trio whole-exome sequencing and a gene matching approach, we identified a cohort of 18 male individuals from 17 families with hemizygous variants in KCND1, including two de novo missense variants, three maternally inherited protein-truncating variants, and 12 maternally inherited missense variants. Affected subjects present with a neurodevelopmental disorder characterized by diverse neurological abnormalities, mostly delays in different developmental domains, but also distinct neuropsychiatric signs and epilepsy. Heterozygous carrier mothers are clinically unaffected. KCND1 encodes the α-subunit of Kv4.1 voltage-gated potassium channels. All variant-associated amino acid substitutions affect either the cytoplasmic N- or C-terminus of the channel protein except for two occurring in transmembrane segments 1 and 4. Kv4.1 channels were functionally characterized in the absence and presence of auxiliary ß subunits. Variant-specific alterations of biophysical channel properties were diverse and varied in magnitude. Genetic data analysis in combination with our functional assessment shows that Kv4.1 channel dysfunction is involved in the pathogenesis of an X-linked neurodevelopmental disorder frequently associated with a variable neuropsychiatric clinical phenotype.

Genetic association of APOA5 and APOE with metabolic syndrome and their interaction with health-related behavior in Korean men.

BACKGROUND: Genome-wide association studies have been used extensively to identify genetic variants linked to metabolic syndrome (MetS), but most of them have been conducted in non-Asian populations. This study aimed to evaluate the association between MetS and previously studied single nucleotide polymorphisms (SNPs), and their interaction with health-related behavior in Korean men. METHODS: Seventeen SNPs were genotyped and their association with MetS and its components was tested in 1193 men who enrolled in the study at Seoul National University Hospital. RESULTS: We found that rs662799 near APOA5 and rs769450 in APOE had significant association with MetS and its components. The SNP rs662799 was associated with increased risk of MetS, elevated triglyceride (TG) and low levels of high-density lipoprotein, while rs769450 was associated with a decreased risk of TG. The SNPs showed interactions between alcohol drinking and physical activity, and TG levels in Korean men. CONCLUSIONS: We have identified the genetic association and environmental interaction for MetS in Korean men. These results suggest that a strategy of prevention and treatment should be tailored to personal genotype and the population.

Whole genomic approach in mutation discovery of infantile spasms patients.

Infantile spasms (IS) are a clinically and genetically heterogeneous group of epilepsy disorders in early infancy. The genetic backgrounds of IS have been gradually unraveled along with the increased application of next-generation sequencing (NGS). However, to date, only selected genomic regions have been sequenced using a targeted approach in most cases of IS, and the genetic etiologies of the majority of patients remain unknown. We conducted a proof-of-concept study using whole-genome sequencing (WGS) for the genetic diagnosis of IS. We included 16 patients with IS for this study, and WGS was applied as a first-tier test for genetic diagnosis. In total, we sequenced the whole genomes of 28 participants, including the genomes of six patients, which were sequenced with those of their parents. Among variants identified, we focused on those located in epilepsy or seizure-associated genes. We used two different methods to call relevant large deletions from WGS results. We found pathogenic or likely pathogenic variants in four patients (25.0%); a de novo variant in HDAC4, compound heterozygous variants in GRM7, and heterozygous variants in CACNA1E and KMT2E. We also selected two more candidate variants in SOX5 and SHROOM4 intronic regions. Although there are currently several difficulties in applying WGS for genetic diagnosis, especially in clinical interpretation of non-coding variants, we believe that developing sequencing technologies would overcome these hurdles in the near future. Considering the vast genetic heterogeneity and the substantial portion of patients with unknown etiologies, further studies using whole genomic approaches are necessary for patients with IS.

FARS2 mutation and epilepsy: Possible link with early-onset epileptic encephalopathy.

Early-onset epileptic encephalopathy (EOEE) consists of a heterogeneous group of epilepsy phenotypes. Recent technological advances in molecular biology have also rapidly expanded the genotype of EOEE. Genes involved in diverse molecular pathways, including ion channels, synaptic structure, transcription regulation, and cellular growth, have been implicated in EOEE. Mitochondrial aminoacyl tRNA synthetase, which plays a key role in mitochondrial protein synthesis by attaching 20 different amino acids to the tRNA tail, has been recently linked with the epilepsy phenotype. Here, we report a novel homozygous c.925G>A (G309S) missense mutation in the gene that encodes the human mitochondrial phenylalanyl-tRNA synthetase (FARS2) in four patients from two nonconsanguineous Korean families. All four patients suffered from intractable seizures that started at the age of 3 and 4 months. Seizure types were variable, including infantile spasms and myoclonic seizures, and often prolonged. Although their initial development seemed to be normal, relentless regression after seizure onset occurred in all patients. An etiologic investigation, including brain imaging and metabolic studies, did not reveal a specific etiology. We reviewed the epilepsy phenotypes of six additional FARS2 mutation-positive patients and suggest that FARS2 can be considered one of the genetic causes of EOEE.