Expanding the spectrum of KCNJ6-related disorders: Milder phenotype with pathological startle responses

Abstract

Keppen-Lubinsky syndrome is caused by pathogenic variants in KCNJ6, which encodes the inwardly rectifying channel subfamily J6. The four confirmed cases reported to date were characterized by severe intellectual disability, global developmental delay, feeding difficulties, and dysmorphic features. All but one of the cases also had a severe form of lipodystrophy, resulting in tightly adherent facial skin and appearance of premature aging. Here, we describe a 36-year-old female with a de novo pathogenic variant in KCNJ6 (NM_002240.5: c.460G>T; p.(Gly154Cys)) presenting with mild intellectual disability, subtle dysmorphic features, obsessive-compulsive disorder, and an exaggerated startle response. This case indicates that KCNJ6-related disorders should be considered in patients with less pronounced dysmorphic features and milder cognitive impairment, as well as in patients with startle disorders.

Keywords: Girk2; KCNJ6; KCNJ6-related disorders; Keppen-Lubinsky syndrome; case report; startle response.

FIGURE 1

Facial lipodystrophy at 1 and 36 years [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Gene structure, position of Gly154 in the selectivity filter of KCNJ6, and its conservation across species. (A) Gene structure with all reported cases of a KCNJ6‐related disorder in English literature marked in red. (B) KCNJ6 structure (Mus musculus crystal structure; Protein Data Bank number SYO3) visualized with ChimeraX. The channel is composed of four chains (in different colors), potassium ions are shown in purple, Gly154 is shown in red. (C) Close‐up of the KCNJ6 selectivity filter, Gly154 is shown in red. (D) Conservation of the selectivity filter Thr151–Val 159 across different species, Gly154 is marked with a red rectangle; * indicates that the amino acid is conserved across all selected species [Colour figure can be viewed at wileyonlinelibrary.com]