CNOT1 – Vissers-Bodmer Syndrome

Vissers-Bodmer Syndrome (VIBOS) is an autosomal dominant neurodevelopmental disorder characterized by developmental delay, intellectual disability, hypotonia, short stature, and distal skeletal anomalies. Onset occurs in infancy with variable expressivity, often including language-motor impairment and behavioral abnormalities. The first definitive link between heterozygous de novo CNOT1 variants and VIBOS was established in 2019, with 39 unrelated individuals described (PMID:32553196).

Subsequent case series identified three additional de novo CNOT1 variants in Chinese families presenting with global developmental delay, intellectual disability, hypotonia, spina bifida occulta and other anomalies (PMID:38434094). A further report described a child with primary short stature, hypotonia, and a novel de novo base duplication c.316_317dup (p.Pro107SerfsTer10) in exon 5 of CNOT1, expanding the phenotypic spectrum (PMID:37818768). All variants occurred de novo with no evidence of familial segregation beyond probands.

The CNOT1 variant spectrum in VIBOS includes loss-of-function alleles—nonsense, frameshift, and splice site mutations—and missense changes. Representative alleles include c.316_317dup (p.Pro107SerfsTer10) causing protein truncation, and missense variants c.557C>T (p.Ser186Phe) and c.3451A>G (p.Asn1151Asp), each predicted deleterious and observed in unrelated probands.

Functional modeling supports haploinsufficiency or hypomorphic mechanisms: Drosophila knockdown of CNOT1 orthologs recapitulates learning, memory, and motor defects, which are rescued by wild-type human CNOT1 but not by patient-derived mutants (PMID:32553196). In vitro minigene assays demonstrated that the splice variant c.1343+1G>T induces exon 12 skipping in CNOT1 transcripts, with partial rescue achieved via modified U1 snRNA (PMID:37507849).

The consistent de novo occurrence of over 40 rare, deleterious CNOT1 variants in unrelated individuals, combined with concordant functional evidence, fulfills ClinGen Definitive criteria for CNOT1–VIBOS association. There is no significant conflicting evidence to date.

Key Take-home: Heterozygous de novo CNOT1 variants cause autosomal dominant Vissers-Bodmer Syndrome, providing a definitive basis for diagnostic testing and genetic counseling.

References

• American Journal of Human Genetics | 2020 | De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay. PMID:32553196
• American Journal of Medical Genetics. Part A | 2024 | Vissers-Bodmer Syndrome caused by a novel de novo CNOT1 frameshift variant. PMID:37818768
• Heliyon | 2024 | Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome. PMID:38434094
• American Journal of Medical Genetics. Part A | 2023 | Pathogenicity analysis and splicing rescue of a classical splice site variant (c.1343+1G>T) of CNOT1 gene associated with neurodevelopmental disorders. PMID:37507849

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