Dataset Information

Biallelic KCTD3 nonsense variant derived from paternal uniparental isodisomy of chromosome 1 in a patient with developmental epileptic encephalopathy and distinctive features.

ABSTRACT: A biallelic nonsense variant of the potassium channel tetramerization domain-containing protein 3 gene (KCTD3) [c.1192C>T; p.R398*] was identified in a patient with developmental epileptic encephalopathy with distinctive features and brain structural abnormalities. The patient showed isodisomy of chromosome 1, where KCTD3 is located, and the father was heterozygous for the same variant. Based on these findings, paternal uniparental disomy was considered to cause the biallelic involvement of KCTD3.

SUBMITTER: Shimojima Yamamoto K

PROVIDER: S-EPMC10406933 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Biallelic KCTD3 nonsense variant derived from paternal uniparental isodisomy of chromosome 1 in a patient with developmental epileptic encephalopathy and distinctive features.

Shimojima Yamamoto Keiko K Yoshimura Ayumi A Yamamoto Toshiyuki T

Human genome variation 20230807 1

A biallelic nonsense variant of the potassium channel tetramerization domain-containing protein 3 gene (KCTD3) [c.1192C>T; p.R398*] was identified in a patient with developmental epileptic encephalopathy with distinctive features and brain structural abnormalities. The patient showed isodisomy of chromosome 1, where KCTD3 is located, and the father was heterozygous for the same variant. Based on these findings, paternal uniparental disomy was considered to cause the biallelic involvement of KCTD ...[more]

PMID: 37550298

Similar Datasets

Project description:BackgroundThe ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings.ResultsAlthough clinical panel sequencing of genes implicated in nephrotic syndromes yielded no likely causal mutation, an oligo-SNP microarray identified a ~20-Mb region of homozygosity, with no altered gene dosage, on chromosome 16p13. Intersection of the proband's phenotypes with known disease genes within the homozygous region yielded a single candidate, IFT140, encoding a retrograde intraflagellar transport protein implicated previously in several ciliopathies, including the phenotypically overlapping Mainzer-Saldino syndrome (MZSDS). Sanger sequencing yielded a maternally inherited homozygous c.634G>A; p.Gly212Arg mutation altering the exon 6 splice donor site. Functional studies in cells from the proband showed that the locus produced two transcripts: a majority message containing a mis-splicing event that caused a premature termination codon and a minority message homozygous for the p.Gly212Arg allele. Zebrafish in vivo complementation studies of the latter transcript demonstrated a loss of function effect. Finally, we conducted post-hoc trio-based whole exome sequencing studies to (a) test the possibility of other causal loci in the proband and (b) explain the Mendelian error of segregation for the IFT140 mutation. We show that the proband harbors a chromosome 16 maternal heterodisomy, with segmental isodisomy at 16p13, likely due to a meiosis I error in the maternal gamete.ConclusionsUsing clinical phenotyping combined with research-based genetic and functional studies, we have characterized a recurrent IFT140 mutation in the proband; together, these data are consistent with MZSDS. Additionally, we report a rare instance of a uniparental isodisomy unmasking a deleterious mutation to cause a ciliary disorder.

Project description:Early infantile epileptic encephalopathy (EIEE) is a severe neurologic and neurodevelopmental disease that manifests in the first year of life. It shows a high degree of genetic heterogeneity, but the genetic origin is only identified in half of the cases. We report the case of a female child initially diagnosed with Leber congenital amaurosis (LCA), an early-onset retinal dystrophy due to photoreceptor cell degeneration in the retina. The first examination at 9 months of age revealed no reaction to light or objects and showed wandering eye movements. Ophthalmological examination did not show any ocular abnormalities. The patient displayed mildly dysmorphic features and a global developmental delay. Brain MRI demonstrated pontine hypo-/dysplasia. The patient developed myoclonic epileptic seizures and epileptic spasms with focal and generalized epileptiform discharges on electroencephalogram (EEG) at the age of 16 months. Genetic screening for a potentially pathogenic DNA sequence variant by whole-exome sequencing (WES) revealed a novel, conserved, homozygous frameshift variant (c.5391delA, p.(Ala1798LeufsTer59)) in exon 42 of the DOCK7 gene (NM_001271999.1). Further analysis by SNP array (Karyomapping) showed loss of heterozygosity (LOH) in four segments of chromosome 1. WES data of the parents and the index patient (trio analysis) demonstrated that chromosome 1 was exclusively inherited from the mother. Four LOH segments of chromosome 1 alternately showed isodisomy (UPiD) and heterodisomy (UPhD). In WES data, the father was a noncarrier, and the mother was heterozygous for this DOCK7 variant. The DOCK7 gene is located in 1p31.3, a region situated in one of the four isodisomic segments of chromosome 1, explaining the homozygosity seen in the affected child. Finally, Sanger sequencing confirmed maternal UPiD for the DOCK7 variant. Homozygous or compound heterozygous pathogenic variants in the DOCK7 (dedicator of cytokinesis 7) gene are associated with autosomal recessive, early infantile epileptic encephalopathy 23 (EIEE23; OMIM #615,859), a rare and heterogeneous group of neurodevelopmental disorders diagnosed during early childhood. To our knowledge, this is the first report of segmental uniparental iso- and heterodisomy of chromosome 1, leading to homozygosity of the DOCK7 frameshift variant in the affected patient.

Dataset Information

Biallelic KCTD3 nonsense variant derived from paternal uniparental isodisomy of chromosome 1 in a patient with developmental epileptic encephalopathy and distinctive features.

Publications

Biallelic KCTD3 nonsense variant derived from paternal uniparental isodisomy of chromosome 1 in a patient with developmental epileptic encephalopathy and distinctive features.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets