Syndrome related to MYT1L gene haploinsufficiency

Rare genetic disease · Orphanet code 647799

​

MYT1L syndrome is a rare genetic disease, first described in 2011.

It causes a non-degenerative neurodevelopmental disorder that appears in early childhood. Its official designation in the National Diagnosis and Care Protocol (PNDS), published on the website of the French National Authority for Health (HAS) in January 2026, is: "syndrome related to haploinsufficiency of the MYT1L gene."

​

Understanding the mechanism
Haploinsufficiency refers to a mechanism in which one of the two copies of the gene no longer works properly: it no longer produces enough MYT1L protein to fulfil its role in the development of the central nervous system. This protein acts as a "conductor" of neuronal identity.

​

Three types of genetic anomaly can lead to this loss of function:

• The nucleotide variant (formerly a "mutation"): a single-point change in the gene's DNA sequence — a "spelling mistake." It may be truncating (nonsense, frameshift, splicing) or missense.

• The deletion: the loss of part or all of the gene, located at 2p25.3. Only a single, insufficient functional copy then remains.

• Certain duplications: only duplications whose two breakpoints lie within the gene interrupt it and cause a loss of function — to date the only situation in which a duplication leads to MYT1L syndrome. Other duplications retain a complete, functional copy of the gene: they do not cause MYT1L syndrome, are often inherited from an asymptomatic parent, and may be linked to a distinct, poorly defined condition.

 

In every case, it is the reduced expression of MYT1L that causes the syndrome.

 

The syndrome is autosomal dominant with complete penetrance, but variable expressivity: all carriers develop a form of the condition, but its severity differs from one person to another.

​

Genetic diagnosis
The diagnosis is made through genetic testing, usually on a blood sample from the patient and, where possible, both parents (trio analysis).

Depending on the anomaly suspected:

• Molecular cytogenetics (CGH-array, SNP-array) to identify deletions and duplications;

• High-throughput sequencing (NGS) — exome or genome — to identify single-nucleotide variants; genome sequencing can detect both types of anomaly in a single test.

Variant interpretation follows the American College of Medical Genetics and Genomics (ACMG) classification, the international reference ensuring consistent, reliable conclusions. The anomaly most often arises de novo (not found in the parents); more rarely, it is inherited from an affected parent.

​

Prenatal diagnosis
When a genetic variant has already been identified in a family member, targeted prenatal diagnosis is possible, within personalised genetic counseling.

​

Genetic counseling
A person carrying MYT1L syndrome has a 50% probability of passing the anomaly on to each of their children. For a non-carrier couple whose first child has a de novo anomaly, the risk of recurrence in a future pregnancy is very low.

​

Differential diagnoses
MYT1L syndrome is rarely suspected on clinical examination alone, as its features are non-specific.

According to the PNDS, the main differential diagnoses are:

• Prader-Willi syndrome (eating behaviour disorder, hyperphagia, behavioural difficulties, intellectual disability);

• 16p11.2 deletions (often associated with autism spectrum disorder and weight problems);

• other neurodevelopmental syndromes combining developmental, behavioural and/or weight difficulties.

In almost all cases, genetic testing establishes the diagnosis.

​

Warning signs
According to the PNDS, several of the following signs together should prompt a genetics consultation:

• global developmental delay, predominantly affecting language and communication;

• persistent global hypotonia;

• autism spectrum disorder;

• attention deficit disorder with or without hyperactivity (ADHD);

• intellectual disability or learning disorders;

• behavioural difficulties (stereotypies, impulsivity, low frustration tolerance, self- or other-directed aggression, anxiety, social disinhibition);

• early weight gain (around age 3) that may progress to overweight or obesity;

• eating behaviour disorders (hyperphagia, lack of satiety, tachyphagia, food impulsivity, oral/feeding aversion).