MYT1L: one gene, many diagnoses

A child with a rare genetic condition can collect diagnoses from several clinics: developmental delay, autism, attention deficit hyperactivity disorder (ADHD), constipation, obesity. Each label is accurate; none on its own explains the child. A small study of MYT1L-related neurodevelopmental disorder shows the pattern well, and makes a case for how rare conditions should be studied.

What the gene is

MYT1L encodes a transcription factor needed for nerve cells to mature. Heterozygous variants (missense, truncating, or deletions at chromosome 2p25.3) cause an autosomal dominant neurodevelopmental disorder; loss of one working copy is thought to be the main mechanism. The largest earlier series, by Coursimault and colleagues in 2022, brought together 62 patients and found developmental delay with language delay in 95%, intellectual disability in 70%, learning disability without intellectual disability in 30%, overweight or obesity in 58%, behavioural disorders in 98% and epilepsy in 23%.

What the study did

Jorge Granadillo, Joseph Dougherty, John Constantino and colleagues used the Brain Gene Registry, a US research consortium platform that pairs each participant's genetic result with health record data and a standard, remotely delivered assessment battery.

They analysed 25 people with MYT1L-related disorder, using virtual versions of the Shipley (nonverbal cognition), Developmental Profile-4, Child Behavior Checklist and Vineland-3 (adaptive behaviour), and compared them with the rest of the registry: people with variants in other brain genes. Diagnosis codes were available for 10 people and medication data for 5.

What it found

• Cognition and adaptive function: marked difficulties with nonverbal cognition and adaptive skills, particularly motor skills, communication and daily living.
• Behaviour: raised scores for autism, ADHD, conduct problems, oppositional behaviour and anxiety.
• Health records (10 people): frequent codes for developmental delay, speech and language disorder, intellectual disability, gastrointestinal problems and obesity.
• Medication (5 people): alpha-2 adrenergic agonists and laxatives were commonly prescribed.

Caveats

• Very small numbers. Twenty-five overall, 10 with diagnosis data, 5 with medication data. One person changes a percentage by a large amount.
• The comparison group is not the general population but people with other rare genetic conditions, who also have high rates of delay and behavioural difficulty.
• Who joins a registry. Families who sign up are not a random sample, and milder, untested cases are missed.
• One snapshot across mixed ages cannot show how the condition changes over time.
• Prescribing is not effectiveness. That alpha-2 agonists and laxatives were common shows what clinicians prescribed, not what worked.
• This summary rests on the published abstract; the full paper is behind a paywall. A December 2025 preprint described 20 participants, 14 with pathogenic or likely pathogenic variants. The published cohort is 25, so I have not quoted preprint figures.

What it means in clinic

The central lesson is one I return to throughout The Genetics of Autism: a gene does not map onto a single diagnosis. MYT1L variants are associated with learning disability, autism, ADHD, anxiety, obesity and gut problems, in different combinations in different people. In the Coursimault series 30% had learning difficulties without intellectual disability, so a normal-range intelligence quotient (IQ) does not rule the condition out.

Illustrative example only, a composite and not a case from the paper. A seven-year-old has developmental delay, autism diagnosed at four, ADHD at six, chronic constipation and weight crossing upwards through the centiles. Seen one clinic at a time, each problem has its own explanation. Seen together with a genetic result, they form a recognisable pattern.

Practical points:

• When a child has developmental delay or learning disability plus autism, a genetic result is worth having where testing is indicated. It can explain the combination, end the search for other causes, and connect a family with others.
• For MYT1L specifically, watch weight and appetite from early on, and ask about constipation at each review. Both are common and treatable, and both affect behaviour and sleep.
• Alpha-2 agonists being common in this group fits with ADHD symptoms and sleep or arousal problems, but there is no trial evidence specific to MYT1L. Standard ADHD guidance still applies.
• Expect differences between children. The same variant does not give the same picture in every child.

Why registries matter

For a condition with only a hundred or so reported patients, no clinic sees enough patients to learn the natural history, and case reports favour striking presentations. A registry with standard measures, collected the same way for everyone and linked to the health record, is the realistic route to proper numbers and the groundwork for any treatment trial.

The weakness is that registries depend on families finding them. For UK families, the clinical genetics team and condition-specific support groups are the usual route in.

Reference

1. Granadillo JL, Kaster L, Lanzotti V, Grewal D, Schreiber A, Abbacchi AM, Gurnett CA, Kroll KL, Baldridge D, Hazlett HC, DaWalt L, Constantino JN, Gupta A, Dougherty JD. Neurobehavioral profiles and clinical consequences of MYT1L-related neurodevelopmental disorder: insights from the Brain Gene Registry. American Journal of Medical Genetics Part A. Published online 19 October 2026. doi:10.1002/ajmg.a.70321. https://doi.org/10.1002/ajmg.a.70321
2. Coursimault J, Guerrot AM, Morrow MM, et al. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects. Human Genetics. 2022;141(1):65–80. doi:10.1007/s00439-021-02383-z

My book, The Genetics of Autism, covers this in more depth: The Genetics of Autism (Amazon UK).