De Novo Variant in the KCNJ9 Gene as a Possible Cause of Neonatal Seizures

Abstract

Background: The reduction in next-generation sequencing (NGS) costs allows for using this method for newborn screening for monogenic diseases (MDs). In this report, we describe a clinical case of a newborn participating in the EXAMEN project (ClinicalTrials.gov Identifier: NCT05325749).

Methods: The child presented with convulsive syndrome on the third day of life. Generalized convulsive seizures were accompanied by electroencephalographic patterns corresponding to epileptiform activity. Proband WES expanded to trio sequencing was performed.

Results: A differential diagnosis was made between symptomatic (dysmetabolic, structural, infectious) neonatal seizures and benign neonatal seizures. There were no data in favor of the dysmetabolic, structural, or infectious nature of seizures. Molecular karyotyping and whole exome sequencing were not informative. Trio WES revealed a de novo variant in the KCNJ9 gene (1:160087612T > C, p.Phe326Ser, NM_004983), for which, according to the OMIM database, no association with the disease has been described to date. Three-dimensional modeling was used to predict the structure of the KCNJ9 protein using the known structure of its homologs. According to the predictions, Phe326Ser change possibly disrupts the hydrophobic contacts with the valine side chain. Destabilization of the neighboring structures may undermine the formation of GIRK2/GIRK3 tetramers necessary for their proper functioning.

Conclusions: We believe that the identified variant may be the cause of the disease in this patient but further studies, including the search for other patients with the KCNJ9 variants, are needed.

Keywords: GIRK; KCNJ9; neonatal seizure; trio; whole exome sequencing (WES).

Figure 2

Homology modeling of GIRK3. (a) Modeled GIRK3 subunit. The template GIRK2 structure (3sya, tetrameric assembly) is shown in white, and GIRK3 is shown in lime. (b) Molecular environment of the residue 326 in GIRK3 (colored by atom type) and GIRK2 (white). (c) Phe326Ser substitution in GIRK3. The GIRK2 subunit (3sya) comprising the glutamate residue is shown in white. The figure was prepared using VMD [29].

Figure 3

Multiple sequence alignment of human GIRK3 and its close homologs (UniProt entries P48051, Q92806, P63252, and Q14500). Residues 219, 303, 326, and 328 (GIRK3 numbering) are marked with asterisks.

Figure 1

Variant view in the proband and parents in IGV viewer showing its de novo origin.