Novel CIC variants identified in individuals with neurodevelopmental phenotypes

Abstract

Heterozygous pathogenic variants in CIC, which encodes a transcriptional repressor, have been identified in individuals with neurodevelopmental phenotypes. To date, 11 CIC variants have been associated with the CIC-related neurodevelopmental syndrome. Here, we describe three novel and one previously reported CIC variants in four individuals with neurodevelopmental delay. Notably, we report for the first time a de novo frameshift variant specific to the long isoform of CIC (CIC-L, NM_001304815.1:c.1100dup, p.Pro368AlafsTer16) in an individual with speech delay, intellectual disability, and autism spectrum disorder. Our investigation into the function of CIC-L reveals that partial loss of CIC-L leads to transcriptional derepression of CIC target genes. We also describe a missense variant (NM_015125.3:c.683G>A, p.Arg228Gln) in an individual with a history of speech delay and relapsed pre-B acute lymphoblastic leukemia. Functional studies of this variant suggest a partial loss of CIC transcriptional repressor activity. Our study expands the list of CIC pathogenic variants and contributes to the accumulating evidence that CIC haploinsufficiency or partial loss of function is a pathogenic mechanism causing neurodevelopmental phenotypes.

Genome Sequencing of Idiopathic Speech Delay

“…However, the presence of the p.R100W variant in gnomAD, conflicting interpretations in ClinVar, and its location outside hotspots with recurrent pathogenic variants [67] led it to be classified as a variant of unknown significance. Variants in CIC have been associated with a neurodevelopmental disorder characterized by intellectual disability, autism, and ADHD [58,60] (MIM: 617600; Figure 2), with several pLoF variants and one missense variant in the HMG-box domain described. Because the missense variant in CIC identified here is not located in the HMG-box domain, it was classified as variant of unknown significance.…”

“…To our knowledge, this study provides the first case of a SETD1A disorder where only speech delay is the symptom, in the absence of other syndromic features. Prior cases have been reported with developmental delay, intellectual disability, Variants identified in this study are visualized above linear protein schematics; the variants previously published as causal for a monogenic neurodevelopmental disorders are visualized below for SETD1A [13,14,17,47], NAA15 [53][54][55], SPTBN1 [50,51], and ARF3 [52,56] and the short and long isoform of CIC [57][58][59][60] Human Mutation subtle facial dysmorphisms, behavioural problems, early-onset epilepsy, schizophrenia, and/or CAS [13,14,17,47,74,75]. Notably, speech or language delays, although typically not well defined, have been observed in the majority of reported SETD1A disorder cases, but never as the sole symptom.…”

“…Figure2: Locations of identified variants and an overview of published variants in four genes. Variants identified in this study are visualized above linear protein schematics; the variants previously published as causal for a monogenic neurodevelopmental disorders are visualized below for SETD1A[13,14,17,47], NAA15[53][54][55], SPTBN1[50,51], and ARF3[52,56] and the short and long isoform of CIC[57][58][59][60]. Missense variants are indicated in purple and pLoF variants in red.…”