What is TAOK1?

In brief

TAOK1 is a gene located on chromosome 17 that carries the “instructions” for making a protein called TAO1 kinase – an enzyme essential for normal brain development. When a pathogenic variant (change) occurs in one of the two copies of this gene, the protein does not work as it should. The result is TAOK1-associated neurodevelopmental disorder (TAOK1-NDD for short), listed in the OMIM classification under number #619575.

It is a very rare genetic condition – the first cases were scientifically described only in 2019, and the total number of patients documented in the medical literature to date is fewer than one hundred people worldwide. The true number of people with TAOK1-NDD is almost certainly higher, because the diagnosis requires advanced genetic testing that is still not performed routinely.

The TAOK1 gene and its role in the body

Each of us has two copies of the TAOK1 gene – one from each parent. The gene encodes a protein belonging to a group of enzymes called serine/threonine kinases from the TAO kinase family (Thousand And One amino acid kinase – the name comes from the length of the protein, which is 1,001 amino acids). Two related proteins belong to the same family: TAOK2 and TAOK3.

TAO1 kinase performs several key functions in cells. Scientific research has shown that it:

  • regulates the cell’s cytoskeleton, including microtubules – the internal “scaffolding” along which substances are transported inside neurons and which gives cells their shape;
  • acts in the MAPK signaling cascade – one of the most important signal transduction pathways in the cell, regulating growth, maturation, and responses to stimuli;
  • is essential for the proper migration of neurons during development of the cerebral cortex – in mouse studies, silencing the Taok1 gene during the fetal period caused serious disruptions in the journey of neurons to the correct cortical layers;
  • participates in neuronal maturation and the development of the dendritic tree, i.e., the branches through which neurons receive signals from other nerve cells;
  • plays a role in maintaining chromosomal stability during cell division.

Put simply: TAOK1 is one of the “construction engineers” of the developing brain. It helps neurons reach the right place, mature, and connect with other neurons.

What happens when the TAOK1 gene doesn’t work properly?

In people with TAOK1-NDD, one of the two copies of the gene contains a pathogenic variant. Various types of such changes have been described:

  • protein-truncating variants (nonsense, frameshift, or splice-affecting variants) – these mean that no functional protein is produced from the damaged copy of the gene; the cell is then left with only half the normal amount of TAO1 kinase (a mechanism called haploinsufficiency);
  • missense variants – a change of a single amino acid in the protein; in the largest published study, most such variants clustered in the protein’s kinase domain – its enzymatic “engine” – at sites that are particularly intolerant to change;
  • deletions covering part or all of the gene.

Laboratory studies have shown that TAO1 kinase activity must be precisely controlled – both its deficiency and its dysregulation disrupt the normal functioning of neurons.

Where does the variant come from? Inheritance

In most described cases, the variant in the TAOK1 gene arose de novo – that is, as a new, spontaneous change that appeared in a reproductive cell of one of the parents or at a very early stage of embryonic development. It is no one’s fault – such changes cannot be predicted or prevented.

However, cases of the variant being inherited from a parent have also been described. In 2022, the first sibling pair was documented who inherited a TAOK1 variant from a mother with very mild symptoms (minor learning difficulties). This means that TAOK1-NDD shows incomplete penetrance and variable expressivity – the same genetic change can produce symptoms of very different severity in different people, even within one family, ranging from barely noticeable to significant.

The disorder is inherited in an autosomal dominant manner – a variant in one copy of the gene is enough. A person carrying the variant has a 50% chance of passing it on to each child. Families are always advised to seek genetic counseling.

How does TAOK1-NDD present?

The clinical picture is highly variable — from mild learning difficulties to significant intellectual disability. The data below come primarily from the largest study published to date (Elkhateeb et al., Genetics in Medicine, 2025), which included 50 individuals with TAOK1 variants, as well as from earlier publications describing a total of several dozen additional patients.

Development and cognitive functioning

  • Neurodevelopmental abnormalities occurred in 100% of described patients – this is the core feature of the condition. In various combinations, they include: delayed motor development, delayed speech and language development, learning difficulties, and intellectual disability ranging in severity from borderline to severe.
  • A characteristic observation is that many children catch up on motor developmental milestones over time (sitting, walking), while speech and language difficulties persist longer – in studies, they were found in the majority of children assessed after the age of 3.
  • In some individuals, autism spectrum disorder or autistic traits have been described (approx. 31% in the 2025 cohort), as well as ADHD and other behavioral difficulties, and in isolated individuals anxiety, depressive, or mood disorders.

Physical and neurological features

  • Macrocephaly (head circumference more than 2 standard deviations above the mean) – found in 83% of patients in the 2025 cohort; present at birth in some children.
  • Hypotonia (reduced muscle tone) – in 58% of patients; often noticeable already in infancy and potentially affecting motor development.
  • Feeding difficulties in the neonatal period and infancy – one of the most frequently recurring early symptoms; gastroesophageal reflux and other gastrointestinal problems have also been reported.
  • Joint hypermobility (laxity) – common; it may co-occur with hypotonia and affect motor skills.
  • Subtle, shared facial features – including frontal bossing, downslanting palpebral fissures, a long philtrum, and a bulbous nasal tip. These features are usually subtle.
  • Epileptic seizures are rare – in the 2025 cohort of 50 patients, they were reported in 4 individuals (one of whom had a second genetic diagnosis explaining the epilepsy).
  • Brain imaging (MRI) revealed abnormalities in some patients – most commonly enlargement of the ventricular system (ventriculomegaly); less commonly, abnormalities of the corpus callosum, white matter, or cerebellum, among others. In many individuals, brain imaging is normal.
  • Growth abnormalities have also been described, and the most recent study reported episodes of hypoglycemia and genital anomalies in boys as new elements of the clinical picture.
  • Heart defects and stereotypical hand movements have been reported less frequently (in isolated patients).

Important: no person with TAOK1-NDD has all of the symptoms listed above. The severity of the condition varies greatly — even among members of the same family with an identical variant. The list above describes the spectrum of what has been observed in the scientific literature so far, not a prognosis for any particular child.


How is the diagnosis made?

The symptoms of TAOK1-NDD (developmental delay, hypotonia, feeding difficulties) are non-specific – they occur in hundreds of different genetic disorders. For this reason, the diagnosis cannot be made on the basis of the clinical picture alone.

The diagnosis is made using next-generation genetic testing:

  • exome sequencing (WES) or whole-genome sequencing (WGS) – it is these methods that led to the identification of nearly all known patients;
  • ideally as a trio test (child + both parents), which makes it possible to establish right away whether the variant arose de novo or was inherited;
  • detected variants are classified according to international criteria and submitted to databases such as ClinVar, which helps other families and clinicians around the world interpret their results.

Because cases inherited from mildly affected parents have been described, once a variant is detected in a child, testing of the parents is also recommended – this matters for genetic counseling and for assessing risk in future pregnancies.

Can TAOK1-NDD be treated?

At present, there is no causal treatment – no therapy yet repairs the effects of a variant in the TAOK1 gene. Patient care is symptomatic and multidisciplinary, tailored to individual needs, and may include:

  • early developmental intervention and regular physical therapy (for hypotonia and joint laxity),
  • speech and language therapy and alternative/augmentative communication methods — particularly important, because language difficulties are among the most persistent symptoms,
  • feeding support in early life and gastroenterological care for gastrointestinal problems,
  • neurological care (including treatment of epilepsy, if present) and periodic developmental assessment,
  • psychological and educational support, and therapy targeting autism spectrum disorder or ADHD where these have been diagnosed,
  • consultations with other specialists depending on symptoms (cardiologist, endocrinologist, orthopedist).

The good news is that knowledge about TAOK1 is growing very quickly. Advances in genetic medicine – including research into gene therapies for rare neurodevelopmental disorders – provide real grounds for hope that treatments targeting the cause of the condition will emerge in the future. Bringing that day closer is the mission of our foundation.

A brief history of discovery

  • 2019 – the team of Dulovic-Mahlow et al. describes the first 8 patients with de novo TAOK1 variants and neurodevelopmental disorders, identifying TAOK1 as a new disease gene (American Journal of Human Genetics).
  • 2021 – the international study by van Woerden et al. (Human Mutation) confirms the causal link, defines the core phenotype, and demonstrates in animal models that TAOK1 is essential for neuronal maturation and cortical development. The disorder receives an OMIM classification number (#619575).
  • 2022 – Hunter et al. (Cold Spring Harbor Molecular Case Studies) describe the first familial cases, including siblings with a variant inherited from a mildly affected mother, documenting the condition’s incomplete penetrance and variable expressivity.
  • 2025 – Elkhateeb et al. publish in Genetics in Medicine the largest cohort to date: 50 patients and 37 unique variants (including 30 novel ones). The study refines the frequency of individual symptoms and expands the clinical picture with new elements.

This history shows what a young disease entity TAOK1-NDD is – and how much may still happen in the coming years.

Sources

All information on this page comes from peer-reviewed scientific publications and curated genetic databases:

  1. Elkhateeb N. et al. Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder. Genetics in Medicine, 2025;27(3). https://www.gimjournal.org/article/S1098-3600(24)00282-X/fulltext
  2. van Woerden G.M. et al. TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development. Human Mutation, 2021;42(4). https://onlinelibrary.wiley.com/doi/full/10.1002/humu.24176
  3. Hunter J.M. et al. Inherited and de novo variants extend the etiology of TAOK1-associated neurodevelopmental disorder. Cold Spring Harbor Molecular Case Studies, 2022;8(2). https://pmc.ncbi.nlm.nih.gov/articles/PMC8958914
  4. Dulovic-Mahlow M. et al. De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders. American Journal of Human Genetics, 2019. https://www.sciencedirect.com/science/article/pii/S0002929719301910
  5. OMIM #619575 — Developmental delay with or without intellectual impairment or behavioral abnormalities (DDIB). https://omim.org/entry/619575
  6. ClinGen — TAOK1 dosage sensitivity curation. https://search.clinicalgenome.org/kb/gene-dosage/HGNC:29259
  7. Unique — Rare Chromosome Disorder Support Group: TAOK1-related neurodevelopmental disorder (family guide, 2025). https://rarechromo.org/media/singlegeneinfo/Single%20Gene%20Disorder%20Guides/TAOK1-related%20neurodevelopmental%20disorder%20FTNW.pdf

This content is for informational purposes only and does not replace medical advice. Last updated: August 2026.