Case Report: A Case of Epileptic Disorder Associated With a Novel CNTN2 Frameshift Variant in Homozygosity due to Maternal Uniparental Disomy

Abstract

Background: Contactin 2, encoded by CNTN2 on chromosome 1q32.1, is a neural-specific glycoprotein and plays important roles in neurodevelopment. A deleterious homozygous variant in the CNTN2 gene was previously reported to cause autosomal recessive cortical myoclonic tremor and epilepsy. Since then, there has been no further report confirming the association of CNTN2 and epilepsy. Here, we reported one new case, who presented with epilepsy, carrying a novel homozygous frameshift variant in CNTN2. The clinical and genetic features of the patient were reviewed.Case presentation: The male patient presented with preschool age-of-onset neurodevelopmental impairment and focal seizures of temporal origin, and responded to valproate. A trio-whole exome sequencing revealed a novel homozygous frameshift variant in CNTN2 (c.2873_c.2874delCT, p.Thr958Thrfs). The patient’s mother was a heterozygous carrier while his father was wild-type; they were both unaffected and non-consanguineous. Further study revealed that maternal uniparental disomy (1q32.1) unmasked the heterozygous variant of CNTN2 in the proband.Conclusions: This case enhanced the gene–disease relationship between CNTN2 and epilepsy, which will help to further understand this emerging disorder.

Routine Diagnostics Confirm Novel Neurodevelopmental Disorders

“…Contactin-2 is a neuronal membrane protein contributing to the organisation of axonal domains, and variants in the corresponding gene CNTN2 (HGNC:2172, MIM *190197) have been associated with autosomal recessive myoclonic epilepsy [ 16 ]. The phenotypic association is, however, still provisional in OMIM, and currently only the initial study by Stogmann et al [ 16 ] and one case report are available [ 17 ].…”

Whole exome sequencing identified five novel variants in CNTN2, CARS2, ARSA, and CLCN4 leading to epilepsy in consanguineous families

“…It works together with contactin-associated protein-like 2 to form a scaffold that accumulates voltage-gated potassium channels at the juxtaparanodes, which are crucial for maintaining membrane potential and modulating action potential frequency during repetitive firing. To date, 13 mutations in the CNTN2 have been associated with epilepsy and FAME5, including 7 missense mutations, splice variants, and 2 small deletions ( Chen et al, 2021 ). In the present study, we have identified a missense homozygous variant CNTN2 c.1699G>T in 3 diseased individuals of the affected family EP-4, that leads to a change in the amino acid p.Glu567Ter in the 6th laminin G-like C domain of the CNTN2 protein (NP_005067.1).…”

First report of paternal uniparental disomy of chromosome 8 with SLC52A2 mutation in Brown-vialetto-van laere syndrome type 2 and an analysis of genotype-phenotype correlations

“…The UPD can cause disease not only through imprinting defects but also through homozygous exposure to recessive genes ( Chen et al, 2021 ). It is currently believed that imprinted genes exist on chromosomes 6, 7, 11, 14, 15, and 20 (Patten et al, 2014).…”