CUX1-related neurodevelopmental disorder: Deep insights into phenotype-genotype spectrum and underlying pathology

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished cases). A Cux1+/− mouse model was used to analyze CUX1 expression in the brain and evaluate susceptibility to epilepsy. We describe 34 patients with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development, and intellectual disability. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was also reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some patients, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. Furthermore, the balance of CUX1 isoform expression in the brain during development appears to be important for this favorable clinical course.

GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

“…GMDB-FAIR has been used to develop many NGP approaches 19,[35][36][37] for predicting rare disorders after the first usage in GestaltMatcher in 2022. Moreover, GMDB-FAIR data can be used in the research platform (Supplementary Note) to validate the results shown in the published works [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] that provides transparency to the researcher using GestaltMatcher and the probability to extend the existing research with the user's additional data.…”

“…For example, Ebstein et al showed that facial dysmorphism was heterogeneous among the entire PSMC3 patient cohort, but facial similarities were found in patients sharing the same pathogenic variants 39 . To date, 15 publications have analyzed the facial phenotype of the cohort with the GMDB-FAIR dataset and GestaltMatcher [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] . All results can be reproduced in the research platform of GMDB, which we introduce in the Methods section (Figure 2c, Figure 3c and Supplementary Note).…”

Cocaine-Induced Gene Regulation in D1 and D2 Neuronal Ensembles of the Nucleus Accumbens Revealed by Single-Cell RNA Sequencing

“…These include motifs for TRPS1, ZNF652, and CUX2 (Figure 6F). CUX1 and CUX2 are homeodomain TFs that control dendritic branching, spine morphology, and synapse formation 87,88 . Together, these findings provide a comprehensive view of the transcriptional landscape within this withdrawal-associated subpopulation of D1 MSNs, highlighting the molecular mechanisms and regulatory networks that govern the unique adaptations observed during prolonged withdrawal from chronic cocaine.…”

GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

“…For example, Ebstein et al showed that facial dysmorphism was heterogeneous among the entire PSMC3 patient cohort, but facial similarities were found in patients sharing the same pathogenic variants 34 . Deploying this method within our research platform has facilitated the quantification of similarity across 18 cohorts, with 15 already published 34,[44][45][46][47][48][49][50][51][52][53][54][55][56][57] .…”