Clinical characteristics.

The features of CNOT1-related Vissers-Bodmer syndrome (CNOT1-VIBOS) comprise a spectrum, including developmental delay / intellectual disability (mild to profound; some individuals have normal intelligence), infantile hypotonia that typically improves or resolves with age, infant feeding difficulties / dysphagia, epilepsy of varying types, nonspecific brain malformations (including holoprosencephaly in those who have the c.1603C>T [p.Arg535Cys] pathogenic variant), neurobehavioral manifestations (autism, ADHD, OCD), growth issues (both undergrowth and overgrowth have been described), agenesis of the pancreas with resulting neonatal diabetes (primarily in those who have the c.1603C>T [p.Arg535Cys] pathogenic variant), dental anomalies, myopia, strabismus, hearing loss (both conductive and sensorineural), and congenital heart defects. Rarer findings may include spasticity, ataxia, and/or dysarthria, growth hormone deficiency, hypertrichosis, sleep disturbance, and kidney anomalies. While affected individuals may have dysmorphic features, these are usually nonspecific.

Diagnosis/testing.

The diagnosis of CNOT1-VIBOS is established in a proband with suggestive findings and a heterozygous pathogenic variant in CNOT1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment is suggested for developmental delay / intellectual disability, epilepsy, spasticity, ataxia, joint contractures, scoliosis, neonatal diabetes, dental anomalies, myopia, strabismus, hearing loss, and cardiovascular anomalies. Feeding therapy is recommended for poor weight gain; a gastrostomy tube may be considered in those who have dysphagia or persistent feeding issues. Speech-language therapy and consideration of augmentative or alternative communication device for dysarthria. Growth hormone therapy for those who have growth hormone deficiency.

Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; assess for new manifestations such as seizures, changes in tone, movement disorders, and dysarthria; monitor those with seizures as clinically indicated; assess developmental progress and educational needs; monitor for anxiety, ADHD, autism, OCD, aggression, and self-injury; and assess mobility and self-help skills. Dental evaluation at least every six months after tooth eruption. Ophthalmology and audiology evaluations annually or as clinically indicated.

Genetic counseling.

CNOT1-VIBOS is an autosomal dominant disorder. Most probands whose parents have undergone molecular genetic testing have the disorder as a result of a de novo CNOT1 pathogenic variant. Rarely, individuals diagnosed with CNOT1-VIBOS have the disorder as the result of a CNOT1 pathogenic variant inherited from a parent. Affected individuals can have mild intellectual disability or, rarely, normal cognition. If a parent of the proband is known to have the CNOT1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the CNOT1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

CNOT1-VIBOS should be considered in probands with the following clinical and brain MRI findings and family history.

Clinical findings

• Mild-to-profound developmental delay (DD) or intellectual disability (ID). However, rarely, affected individuals can have normal intelligence.

AND

• Any of the following features presenting in infancy or childhood:
  • Generalized hypotonia
  • Epilepsy, such as generalized intractable seizures or intractable complex partial seizures
  • Spasticity
  • Ataxia
  • Dysarthria
  • Neurobehavioral/psychiatric manifestations, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, aggression, impulsivity, stereotypies, repetitive behavior, and/or self-mutilation
  • Cardiovascular anomalies, such as coarctation of the aorta
  • Agenesis of the pancreas leading to neonatal diabetes mellitus (See Genotype-Phenotype Correlations.)
  • Nonspecific dysmorphic features (See Clinical Characteristics.)

Brain MRI findings. Semilobar holoprosencephaly (See Genotype-Phenotype Correlations.)

Family history. Because CNOT1-VIBOS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of CNOT1-VIBOS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in CNOT1 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous CNOT1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome sequencing / genome sequencing [Manickam et al 2021, van der Sanden et al 2023]. Other options include use of a multigene panel. Note: Single-gene testing (sequence analysis of CNOT1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability multigene panel that includes CNOT1 and other genes of interest (see Differential Diagnosis) may identify the genetic cause of the condition in a person while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) Given the rarity of CNOT1-VIBOS, some panels for intellectual disability may not include this gene. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is commonly used and yields results similar to an intellectual disability multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. To date, the majority of CNOT1 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing. Genome sequencing is also possible. ACMG and the American Academy of Pediatrics recommend exome/genome sequencing as first- or second-tier diagnostic testing for children with developmental delay, intellectual disability, and/or multiple congenital anomalies [Manickam et al 2021, Rodan et al 2025].
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

To date, at least 45 individuals have been identified with a pathogenic variant in CNOT1 [De Franco et al 2019, Kruszka et al 2019, Vissers et al 2020, Cospain et al 2022, Dong et al 2023, de Queiroz Júnior et al 2024, Tang et al 2024, Wu et al 2024, Liu et al 2025, Tompa et al 2025]. The following description of the phenotypic features associated with this condition is based on these reports.

Facial features. While many individuals have been described as having dysmorphic features, these are generally nonspecific and not a component of a recognizable phenotype.

Developmental delay (DD) and intellectual disability (ID). The spectrum of cognitive outcomes can vary significantly from none to profound cognitive impairment in those who have holoprosencephaly (see Genotype-Phenotype Correlations).

• Motor delay range from delayed motor milestones (i.e., walking at age two years) to no delay at all.
• Speech skills range from no speech, to being able to utter a few single words at age seven years, to receptive and expressive language impairment, to no delay at all.

Other neurodevelopmental features

• Hypotonia is typically present in infancy but improves or resolves with time.
• Infant feeding difficulties, including dysphagia, are observed in about half of affected individuals and can persist, with at least one affected individual requiring G-tube feeding until age 16 years (see Management). Affected individuals may also have excessive drooling.
• Affected individuals may display spasticity (4/34 affected individuals), ataxia (5/32 affected individuals), and/or dysarthria (10/29 affected individuals).

Epilepsy has been reported in 11/15 (73%) affected individuals. These can include febrile seizures, complex focal seizures, Lennox-Gastaut syndrome, and generalized convulsive seizures.

Neuroimaging. There are numerous brain malformations that have been reported on brain MRI.

• The most specific brain abnormality for individuals with the c.1603C>T (p.Arg535Cys) pathogenic variant is holoprosencephaly (see Genotype-Phenotype Correlations).
• Other imaging findings reported in one or two affected individuals each include:
  • Agenesis or hypoplasia of the corpus callosum
  • Heterotopias
  • Pachygyria
  • Ventriculomegaly
  • White matter hyperintensities
  • Arachnoid cysts
  • Chiari I or II malformations
  • Small cerebellum or cerebellar vermis hypoplasia
  • Hypoplasia of brain stem
  • Enlarged Virchow-Robin spaces
  • Frontal lobe dysplasia

Neurobehavioral/psychiatric manifestations. Eleven out of the 31 affected individuals with neurobehavioral manifestations have autism spectrum disorder (ASD); however, attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD) may also be observed. Other features may include:

• Anxiety
• Aggressive behavior
• Impulsivity
• Stereotypies
• Other socioemotional problems

Growth. Growth disturbance most often leads to undergrowth, although overgrowth has more rarely been reported.

• A little more than half of affected individuals have short stature. However, there were two individuals who were taller than average.
• About 20% of affected individuals have microcephaly and two have been reported with macrocephaly.

Musculoskeletal features. It appears that there is not a specific pattern of musculoskeletal features. However, brachydactyly, 5th digit clinodactyly, and tapered fingers occur more often in affected individuals. Specific features that have been reported four times or less:

• Pes vulgus or planus (4 individuals)
• (Mild) scoliosis (2 individuals)
• There are two affected individuals with a broader musculoskeletal phenotype:
  • One had generalized hypermobility with hyperextensible legs, long neck, ability to dislocate the jaw, and easy bruising.
  • The other had arthrogryposis (joints not specified), gracile and elongated long bones with multiple fractures, and dislocated hips with deep dimples on the lateral aspects.

Endocrine features. Specific features that have been reported four times or less:

• Four of the seven individuals with the c.1603C>T (p.Arg535Cys) pathogenic variant had agenesis of the pancreas resulting in neonatal diabetes mellitus.
• Growth hormone deficiency successfully treated with growth hormone therapy has been observed in three affected individuals.

Ectodermal findings. Specific features that have been reported four times or less:

• Hypertrichosis (5 individuals)
• Dental abnormalities, such as delayed tooth eruption, multiple additional teeth, and brownish enamel of secondary dentition can occur.

Ophthalmologic involvement. Myopia and strabismus have been described in multiple affected individuals. Other isolated features that have been reported four times or less:

• Glaucoma
• Ptosis
• Papilledema
• Hypermetropia
• Astigmatism

Hearing impairment. Five affected individuals have been reported with hearing impairment: two with conductive, two with sensorineural, and one with mixed bilateral hearing loss. A CT scan of the latter individual showed ossicle anomalies.

Cardiovascular anomalies have been reported in 8/24 (33%) affected individuals who underwent evaluation. The following have been reported in single individuals:

• Ventriculomegaly and persistent ductus arteriosis
• Coarctation of the aorta
• Hypoplastic left heart with ascending aorta hypoplasia
• Bicuspid aortic valve with mild stenosis
• Aortic root dilatation (it is unclear if this was progressive)

Other rarer reported features. Sleep disturbance, gastrointestinal problems, and genitourinary abnormalities have been observed in one or two affected individuals each. It is unclear whether these features are rare findings in individuals with CNOT1-VIBOS or if these represent rare co-occurrences unrelated to CNOT1-VIBOS.

Prognosis. It is unknown whether life span in individuals with CNOT1-VIBOS is abnormal. One reported individual is alive at age 40 years [Vissers et al 2020], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

Five individuals with the c.1603C>T (p.Arg535Cys) pathogenic variant have semilobar holoprosencephaly and one has lobular holoprosencephaly. Four affected individuals with this pathogenic variant also had pancreatic agenesis with resulting neonatal diabetes mellitus [De Franco et al 2019, Cospain et al 2022, de Queiroz Júnior et al 2024].

Individuals with the c.76C>T (p.Arg26Ter) pathogenic variant are more likely to have mild or no cognitive impairment

Nomenclature

CNOT1-related Vissers-Bodmer syndrome including CNOT1-related holoprosencephaly 12 may also be referred to as CNOT1-related neurodevelopmental disorder based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Prevalence

The prevalence of CNOT1-VIBOS is unknown. There are currently 45 individuals described with a causative pathogenic variant in CNOT1.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CNOT1-VIBOS, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for CNOT1-VIBOS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

The splicing defects caused by a variant that changes the splice acceptor site can potentially be neutralized by using a modified U1 small nuclear RNA [Dong et al 2023]. This is a promising therapy that has not been investigated further.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

CNOT1-related Vissers-Bodmer syndrome (CNOT1-VIBOS) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with CNOT1-VIBOS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CNOT1 pathogenic variant.
• Rarely, individuals diagnosed with CNOT1-VIBOS have the disorder as the result of a CNOT1 pathogenic variant inherited from a parent. Affected individuals can have mild intellectual disability or, rarely, normal cognition.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a CNOT1 pathogenic variant may be mildly/minimally affected [Vissers et al 2020].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the CNOT1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the CNOT1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Vissers et al 2020].

Offspring of a proband. Each child of an individual with CNOT1-VIBOS has a 50% chance of inheriting the CNOT1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is heterozygous for the CNOT1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the CNOT1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CCR4-NOT transcription complex subunit 1 (CNOT1) is the central scaffolding protein of the human CCR4-NOT complex, which consists of up to 11 different subunits [Shirai et al 2014]. Each of the subunits has a specific function. The catalytic activity of CNOT6, CNOT6L, CNOT7, and CNOT8 plays an important role in the deadenylation step leading to mRNA degradation. The E3 ligase activity of CNOT4 is involved in protein substrate recognition and ubiquitination [Albert et al 2002]. In addition to its scaffolding function, CNOT1 has been considered a translational regulator through the binding of nuclear receptors and a regulator of deadenylase activity [Winkler et al 2006, Ito et al 2011]. For the latter, CNOT1 also exhibits the capacity to bind proteins that are not part of the CCR4-NOT complex but are known to either be involved in general or tissue-specific mRNA degradation pathways [Fabian et al 2011, Suzuki et al 2012, Fabian et al 2013, Murakawa et al 2015, Du et al 2016].

Nonsense, splice site, frameshift, and missense pathogenic variants of CNOT1 have been observed in CNOT1-related Vissers-Bodmer syndrome (CNOT1-VIBOS). The missense variants of 16 of 18 individuals suggested clustering to CNOT1 functional domains: six affected the HEAT domain, which modulates substrate specificity; two affected the TTP-binding domain, involved in deadenylation; four affected the CAF1 domain, binding proteins with catalytic properties; four affected a domain of unknown function (DUF3819); and one affected the Not1 domain, which is associated with interaction of multiple protein partners. The variants thereby affect interactions with protein-binding partners, such as the other CNOT proteins.

However, functional characterization of the de novo variants at both the level of RNA and protein, as well as its functional roles in important biological processes such as mRNA decay and cell viability, have not revealed the pathophysiologic mechanisms underlying this neurodevelopmental disorder. Only knockdown and rescue experiments in Drosophila have shown involvement of nonsense and missense variants on neurodevelopment.

Mechanism of disease causation. Loss of function

Author Notes

Arjan de Brouwer (ln.cmuduobdar@rewuorbed.najra) is actively involved in clinical research regarding individuals with CNOT1-related Vissers-Bodmer syndrome (CNOT1-VIBOS). He would be happy to communicate with persons who have any questions regarding diagnosis of CNOT1-VIBOS or other considerations.

Acknowledgments

We wish to thank all families participating in this study. The collaborations described were facilitated by the ERN ITHACA, one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States, co-funded by European Commission. For more information about the ERNs and the EU health strategy visit https://ec.europa.eu/health/ern.

Revision History

• 26 March 2026 (ma) Review posted live
• 14 March 2025 (adb) Original submission

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