CSDE1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2019 (Guo et al., PMID: 31579823). CSDE1-related complex neurodevelopmental disorder is characterized by phenotypic features including autism, intellectual disability, delayed speech and delayed motor development. Less frequently reported phenotypes include sleep disturbances, obsessive behavior, hypotonia and short stature. Fifteen variants (nonsense, frameshift, splicing) that have been reported in 18 probands in 3 publications (PMIDs: 31579823, 33867523, 34519148) are included in this curation. One recurrent variant ( c.367C>T, p.R123*) is found in four unrelated families. Three of the variants are inherited. Each of the carrier parents and siblings either exhibited mild neurodevelopmental phenotypes or presented with substantial family history of autism or developmental disability. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function.
This gene-disease relationship is also supported by animal models and in vitro functional assays (PMID: 315799823). Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission. Additionally, disruption of the CSDE1 homolog gene dUnr interferes with synapse development and transmission in Drosophila (PMID: 31579823). The results in Drosophila models are consistent with the effect of CSDE1 deficiency on synapse development and function in humans.
In summary, there is definitive evidence supporting the relationship between CSDE1 and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectuial Disability and Autism GCEP on November 21, 2023 (SOP Version 10).
CSDE1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2019 (Guo et al., PMID: 31579823). CSDE1-related complex neurodevelopmental disorder is characterized by autism, intellectual disability, delayed speech and delayed motor development. Less frequently reported phenotypes include sleep disturbances, obsessive behavior, hypotonia and short stature. Fifteen variants (nonsense, frameshift, splicing) that have been reported in 18 probands in 3 publications (PMIDs: 31579823, 33867523, 34519148) are included in this curation. One recurrent variant (c.367C>T, p.R123*) is found in four unrelated families. Three of the variants are inherited. Each of the carrier parents and siblings either exhibited mild neurodevelopmental phenotypes or presented with substantial family history of autism or developmental disability. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss-of-function.
This gene-disease relationship is also supported by animal models and in vitro functional assays (PMID: 31579823). Csde1 knockdown in primary mouse cortical neurons leads to neurite overgrowth, abnormal dendritic spine morphology/synapse formation, and impaired synaptic transmission. Additionally, disruption of the Csde1 homolog gene dUnr in Drosophila interferes with synapse development and transmission (PMID: 31579823). The results in Drosophila models are consistent with the effect of CSDE1 deficiency on synapse development and function in humans.
In summary, there is definitive evidence supporting the relationship between CSDE1 and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 21, 2023 (SOP Version 10).
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