CNOT3 – intellectual developmental disorder with speech delay, autism, and dysmorphic facies

CNOT3 encodes a core subunit of the CCR4-NOT complex and heterozygous variants cause intellectual developmental disorder with speech delay, autism, and dysmorphic facies (IDDSADF). Based on 28 unrelated patients across 5 families, segregation in 4 affected relatives, and consistent functional data, the association meets a Strong ClinGen clinical validity criterion.

Genetic evidence supports an autosomal dominant inheritance pattern with 3 affected individuals in a Korean family carrying an in-frame deletion c.2017_2019del (p.Phe673del)([PMID:38179413]), transmission in two additional families ([PMID:32720325]), and three independent Chinese cases with frameshift and splice variants ([PMID:36802310]). Overall, 28 patients from 5 families have been reported, including 4 segregation events ([PMID:38179413],[PMID:32720325]).

The variant spectrum comprises one in-frame deletion, two missense, three frameshift, and one splice-site alteration. For example, c.2017_2019del (p.Phe673del)([PMID:38179413]) lies within the C-terminal domain, while loss-of-function alleles such as c.724del (p.Ser242ProfsTer?)([PMID:36802310]) reduce mRNA via nonsense-mediated decay.

Functional studies demonstrate haploinsufficiency as the primary pathogenic mechanism. Patient-derived mRNA quantifications show significantly reduced CNOT3 transcripts in carriers of c.1058_1059insT and c.387+>C variants ([PMID:36802310]), and minigene assays confirm exon skipping for splice mutations. A co-occurring truncating variant study further refines the IDDSADF phenotype and underscores functional links within developmental pathways ([PMID:34208845]).

No conflicting reports have been identified to dispute the role of CNOT3 in IDDSADF. The combined genetic and experimental evidence underscores a coherent haploinsufficiency mechanism leading to neurodevelopmental impairment, facial dysmorphisms, and autism spectrum features.

Early molecular diagnosis of c.2017_2019del (p.Phe673del) and related alleles enables genetic counseling, informs prognosis, and supports tailored clinical management of IDDSADF.

References

• Neurology Genetics • 2024 • Novel In-Frame Deletion CNOT3 Variant in a Family With Intellectual Developmental Disorder With Speech Delay and Dysmorphic Facies. PMID:38179413
• Clinical Genetics • 2020 • Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies. PMID:32720325
• Neurogenetics • 2023 • Clinical features of CNOT3-associated neurodevelopmental disorder in three Chinese patients. PMID:36802310
• Genes • 2021 • Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype. PMID:34208845

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