CNOT2 – Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies

Haploinsufficiency of CNOT2 underlies a rare neurodevelopmental disorder, Intellectual Developmental disorder with nasal speech, Dysmorphic Facies, and variable Skeletal anomalies (IDNADFS). We report five unrelated probands (three with de novo intragenic variants, one with a multiexon deletion, and one with a 12q15 microdeletion) exhibiting a consistent neurodevelopmental phenotype (5 probands ([PMID:36224108])). Fewer than 20 additional individuals with 12q15 microdeletions encompassing CNOT2, one truncating variant, and two large intragenic deletions have been documented to date ([PMID:36224108]).

The disorder follows an autosomal dominant inheritance pattern, typically arising from de novo loss-of-function events with no affected relatives reported, indicating high penetrance of heterozygous CNOT2 disruption.

Pathogenic variants comprise nonsense and frameshift mutations, intragenic deletions spanning multiple exons, and heterozygous microdeletions at 12q15. All classes of variants are predicted or shown to result in loss of CNOT2 function, supporting a haploinsufficiency mechanism.

Clinically, affected individuals present with global developmental delay/intellectual disability, hypernasal (nasal) speech, distinctive dysmorphic facies, and variable skeletal anomalies such as scoliosis and limb malformations, comprising the core IDNADFS phenotype.

Functional assays in Saccharomyces cerevisiae demonstrate that loss-of-function mutations in the NOT2 ortholog destabilize the CCR4-NOT complex, with severe alleles causing complete complex loss. These results confirm that CNOT2 dosage is critical for complex integrity, consistent with a haploinsufficiency mechanism ([PMID:12215412]).

The genetic and experimental data collectively provide strong evidence for a causal role of CNOT2 haploinsufficiency in IDNADFS. Additional cases and vertebrate models will refine genotype–phenotype correlations. Key take-home: heterozygous loss-of-function variants in CNOT2 should be considered in individuals with neurodevelopmental delay, nasal speech, dysmorphic features, and skeletal anomalies.

References

• Clinical Genetics • 2023 • Delineation of the clinical profile of CNOT2 haploinsufficiency and overview of the IDNADFS phenotype. PMID:36224108
• Journal of Molecular Biology • 2002 • Characterization of mutations in NOT2 indicates that it plays an important role in maintaining the integrity of the CCR4-NOT complex. PMID:12215412

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