Intragenic CAMTA1 deletions are associated with a spectrum of neurobehavioral phenotypes

Abstract

Intragenic copy number variations involving the CAMTA1 (calmodulin-binding transcription activator 1) gene have recently been reported in four unrelated families with intellectual disability (ID), ataxia, behavioral- and cerebellar-abnormalities. We report a detailed phenotypic and molecular characterization of three individuals with novel intragenic CAMTA1 deletions from two unrelated families and compare the findings to those of previously reported patients. Our patients had deletions of exons 6-11 and presented with ID, developmental delay (DD), attention deficit hyperactivity disorder (ADHD) and constipation. Two individuals from one family had also unsteady gait. Consistent phenotypes associated with CAMTA1 intragenic rearrangements include ID, speech problems and some dysmorphic features whereas neurobehavioral abnormalities are variable. We did not observe obvious phenotypic differences between patients with in-frame and those with frameshift rearrangements. There is an increased evidence that CAMTA1 has a role in brain and cerebellar function. CAMTA1 should be added to the growing list of genes associated with ID/DD, especially when behavioral problems, cerebellar signs, and/or dysmorphism are also present.

Sparse multiple factor analysis to integrate genetic data, neuroimaging features, and attention‐deficit/hyperactivity disorder domains

“…Moreover, MFA results associated these findings with two intragenic SNPs (rs301806 and rs12563394) within the CAMTA1 gene, which has been related to episodic tremor and motor impairment (Monies et al, ; Shinawi, Coorg, Shimony, Grange, & Al‐Kateb, ). Interestingly, it has been demonstrated that ADHD children usually present difficulties in activities that require motor coordination (Goulardins, Marques, & De Oliveira, ; Kaiser, Schoemaker, Albaret, & Geuze, ).…”

Multidimensional Genetic Analysis of Repeated Seizures in the Hybrid Mouse Diversity Panel Reveals a Novel Epileptogenesis Susceptibility Locus

“…Increased Camta1 activity is a predictable consequence of inducing repeated seizures, the activity of which would be enhanced by reduced K + buffering capacity that is an aspect of our model. Finally, mutations in CAMTA1 are associated with multiple neurological phenotypes, including seizure susceptibility in humans ( Miller et al 2011 ; Shinawi et al 2015 ). Identifying the basis of this susceptibility will lead to improved diagnosis and novel treatment options for individuals with epilepsy.…”

Association of a Locus in theCAMTA1Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis

“…Intragenic CAMTA1 microrearrangements disrupting a CG-1 DNA-binding domain have been reported to cosegregate with nonprogressive congenital cerebellar ataxia (NPCA) and gait instability in several unrelated families. 27,28 Common variants within CAMTA1 have also been reported to be associated with variation in human episodic memory. 29 Mutant CAMTA1 knockout mice, disrupted in the CG-1 domain, show severe ataxia and neuronal atrophy approximating the phenotype of haploinsufficiency observed in patients with NPCA.…”