Expanding the phenotypic spectrum of CSNK2A1-associated Okur-Chung neurodevelopmental syndrome

Abstract

De novo variants in CSNK2A1 cause autosomal dominant Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS has an evolving clinical phenotype predominantly characterized by intellectual disability, global delays, dysmorphic features, and immunological manifestations. Microcephaly, defined as a small head circumference, is not widely recognized as a classical clinical presentation. Here, we describe four individuals from three unrelated families who shared several clinical features characteristic of an underlying syndromic neurodevelopmental condition. Trio clinical exome and research genome sequencing revealed that all affected individuals had heterozygous pathogenic missense variants in CSNK2A1. Two variants (c.468T>A p.Asp156Glu and c.149A>G p.Tyr50Cys) were de novo and previously reported, but the third variant (c.137G>T p.Gly46Val) is novel and segregated in two affected individuals in a family. This adds to growing evidence of inherited disease-causing variants in CSNK2A1, an observation reported only twice previously. A detailed phenotypic analysis of our cohort together with those individuals reported in the literature revealed that OCNDS individuals, on average, have a smaller head circumference with one-third presenting with microcephaly. We also show that the incidence of microcephaly is significantly correlated with the location of the variant in the encoded protein. Our findings suggest that small head circumference is a common but under-recognized feature of OCNDS, which may not be apparent at birth.

Keywords: CSNK2A1; Okur-Chung; genotype-phenotype; microcephaly; mutations; neurodevelopmental disorders.

Figure 1

OCNDS-associated CSNK2A1 variants identified in this study and the literature (A) Pedigree and CSNK2A1 genotype of the three families described in our study. “+” indicates wild-type (WT) allele. (B and C) FireFly plot visualization of all unique pathogenic/likely pathogenic CSNK2A1 variants reported in ClinVar (as of October 2023) (B) and in the (C) literature (as of October 2023); red arrows highlight the variants reported in this study (p.Gly46Val, p.Tyr50Cys, p.Asp156Glu). (D) Sequence alignment of functional segments within the CSNK2A1 kinase across multiple species (top to bottom: zebrafish, human, bovine, rat, and mouse) using the Clustal Omega program.

Figure 2

OCNDS individuals exhibit microcephaly, and the occurrence of this phenotype is associated with the position of CSNK2A1 variant within the protein (A) Violin plot of occipital frontal circumference (OFC) SDs vs. age of OCNDS individuals reported in the literature. White dashed line indicates median OFC SD value. (B) Co-occurrence of microcephaly with common neurodevelopmental features in OCNDS individuals. Fisher’s exact test, not significant. (C) Prevalence of microcephaly correlates with functional segments within the kinase domain of the CSNK2A1 protein. Chi-squared test, p = 0.020948 (significant at p < 0.05).