A CAMK2B variant associated with tetralogy of Fallot, developmental delay, and growth retardation

CAMK2B encodes the beta-subunit of calcium/calmodulin-dependent protein kinase II (CAMKII), which is expressed mainly in the brain. Variants of CAMK2A and CAMK2B cause neurodevelopmental disorders, and CAMK2B alterations have been described in at least 14 patients with intellectual disability and developmental delay. Here, we describe a novel CAMK2B variant in a patient with tetralogy of Fallot (TOF), developmental delay, and growth retardation. The patient was a 2-year-old female. She was delivered at 36 weeks 6 days gestational age by caesarean section due to non-reassuring fetal status, with birth weight of 1680 g (-2.0 SD), birth length of 43.5 cm (-1.5 SD), and occipital-frontal head circumference (OFC) of 29.4 cm (-1.7 SD). Growth retardation, microcephaly, developmental delay, tetralogy of Fallot, and dysmorphic features were present. The patient controlled her head position at four months, rolled at six months, sat at 13 months, crawled at 18 months, and walked with support at 21 months. She began speaking words at 2 years old. Her dysmorphic features included a wide face, broad forehead, puffy eyelids, broad nasal base, broad and prominent philtrum, pointed chin, full cheeks, and prominent ears. A de novo missense CAMK2B variant (NM_172079.2:c.895A > G (p.Lys299Glu) NC_000007.14:g.44241708T > C (hg38)) was identified by proband exome sequencing and confirmed by Sanger sequencing. The variant was located at an autoregulatory segment and highly conserved among species. This patient displayed many of the physical features of CAMK2B-related neurodevelopmental disorder (NDD), but the TOF present in the current case is not a feature of patients with the NDD. Since a de novo CAMK2B (p.Leu443Val) variant has previously been found in a cohort of TOF, we conclude that CAMK2B variants may be associated with this specific cardiac defect.