A familial case of CAMK2B mutation with variable expressivity

Abstract

Variants in CAMK2-associated genes have recently been implicated in neurodevelopmental disorders and intellectual disability. The clinical manifestations reported in patients with mutations in these genes include intellectual disability (ranging from mild to severe), global developmental delay, seizures, delayed speech, behavioral abnormalities, hypotonia, episodic ataxia, progressive cerebellar atrophy, visual impairments, and gastrointestinal issues. Phenotypic heterogeneity has been postulated. We present a child with neurodevelopmental disorder caused by a pathogenic CAMK2B variant inherited from a healthy mother. A more mildly affected sib was determined to have the same variant. Monoallelic mutations in CAMK2B in patients have previously only been reported as de novo mutations. This report adds to the clinical phenotypic spectrum of the disease and demonstrates intrafamilial variability of expression of a CAMK2B mutation.

Role of Ca2+/Calmodulin-Dependent Protein Kinase Type II in Mediating Function and Dysfunction at Glutamatergic Synapses

“…A heterozygous c.85C>T, p.(Arg29*) mutation in CAMK2B was found in a patient with mild ID, delayed speech development and seizures ( Küry et al, 2017 ). This mutation was also reported in a 3-year-old European girl with complex focal seizures and global neurodevelopmental delay ( Heiman et al, 2021 ). This maternally inherited pathogenic variant of the CAMK2B gene only mildly affected the patient’s sibling, with the same variant, while the mother was phenotypically healthy and intellectually normal ( Heiman et al, 2021 ).…”

“…This mutation was also reported in a 3-year-old European girl with complex focal seizures and global neurodevelopmental delay ( Heiman et al, 2021 ). This maternally inherited pathogenic variant of the CAMK2B gene only mildly affected the patient’s sibling, with the same variant, while the mother was phenotypically healthy and intellectually normal ( Heiman et al, 2021 ). Similarly, a heterozygous c.416C>T, p.(Pro139Leu) variant of CAMK2B found in four Caucasian patients presented with severe ID, global developmental delay, hypotonia and microcephaly ( Küry et al, 2017 ), was also reported in a 22-year-old South Asian woman ( Rizzi et al, 2020 ) as well as in a MECP-2 (methyl-CpG binding protein 2) negative proband of Japanese origin ( Iwama et al, 2019 ).…”

“…The type of mutation (synonymous, missense, splice region, frameshift, deletion), the specific CaMKII isoform (α, β and γ) that is mutated and the protein domain (catalytic, auto-regulatory or association) affected determine the disease phenotype. The zygosity of inheritance (heterozygous/homozygous) can also influence the pathogenicity of the variant ( Chia et al, 2018 ); however, intrafamilial variations in the expression of disease symptoms by subjects carrying the same heterozygous variant, have also been reported ( Heiman et al, 2021 ).…”

Greig Cephalopolysyndactyly Contiguous Gene Syndrome: Case Report and Literature Review

“…The CDK13 and CAMK2B genes have been recently annotated OMIM genes, related to syndromic neurodevelopmental disorders (congenital heart defects, dysmorphic facial features, intellectual developmental disorder associated to MIM# 617360, mental retardation, and autosomal dominant 54 associated to MIM# 617799) [26][27][28][29][30][31][32][33].…”

“…CDK13 codes for a member of the cyclin-dependent serine/threonine protein kinase (STK) family, which phosphorylate targets, such as RNA polymerase II-involved in extracellular and growth signaling [33]. The majority of mutations in CDK13 are missense mutations, occurring within the protein kinase domain leading to significant loss of catalytic activity.…”