What are Chromatinopathies?
Chromatinopathies are a group of rare, congenital disorders caused by mutations in genes that, among other things, disrupt the structure and function of chromatin, the combination of DNA and proteins in the cell nucleus. Such a mechanism falls under the term ‘epigenetics’, a field of science that studies how gene activity can change without changes in the DNA sequence itself. These disruptions can lead to a broad spectrum of developmental disorders and other health problems.
What causes chromatinopathies?
Chromatinopathies are caused by a defect in one of the genes that code for proteins that regulate the epigenome, the so-called epigenes. These genes play a role in rearranging the folding of DNA, and/or switching other genes on or off (regulating gene expression). This means that they influence whether or not other genes are written off. In fact, they ‘direct’ the functioning of other genes. For example, EHMT1, KMT2C, KDM6B, SETD1A and SETD1B in this way important for the proper progression of brain development.
Patients with chromatinopathies often show a combination of developmental problems such as speech-language delay, global developmental delay, intellectual disabilities and autism spectrum disorders, but there may also be abnormalities of organs, such as congenital heart or kidney defects, or problems with the immune system. Such a combination of clinical symptoms, which can vary greatly but have the same cause, is called a syndrome.
How common are chromatinopathies?
Although chromatinopathies are individually rare (estimated to occur in 1:30,000–50,000), they collectively form one of the most important categories within the group of congenital developmental disorders.
Examination and diagnosis
Children with one of the chromatinopathies mentioned below can be referred to the ENCORE Expertise Center by their GP or healthcare provider.
Here they are seen and examined by both a pediatrician specialized in hereditary & congenital Disorders (Dr. Margreth van der Lugt) and a clinical geneticist (Prof. Dr. Tjitske Kleefstra or Dr. Stefan Barakat).
During the consultation, the development in the areas of learning, movement and communication are also evaluated in a structured manner, as well as other common complaints. In addition, a physical examination usually takes place.
De medische specialisten (en paramedici) die het kind onderzoeken hebben veel ervaring met patiënten met (zeldzame) erfelijke ontwikkelingsstoornissen. Maar omdat veel van deze aandoeningen relatief nieuw zijn, zullen we nog lang niet altijd antwoord hebben op alle vragen en zal een bezoek aan ons expertisecentrum met name gericht zijn op het vroegtijdige diagnosticeren, het verzamelen van zo veel mogelijk informatie van patiënten met bepaalde chromatinopathieën en het bieden van multidisciplinaire zorg.
It is therefore not necessarily the intention that the medical care of a child is taken over from the already involved pediatrician or neurologist. The aim is to optimize the care even further through our specific experience.
Epigenetics
The epigenetics consultation hour of the ENCORE Expertise Center is currently every quarter on a Friday morning. When an appointment is made during this consultation hour, an extensive questionnaire is sent prior to the visit to collect as much information as possible, so that the most important concerns can be discussed during the consultation hour. Written permission is also required to request all medical information of a child.
During this consultation, children are seen with a proven or possible genetic defect in one of the epigenes, with the focus currently on;
– EHMT1 or 9q34 deletion (Kleefstra syndrome)
– KMT2C
– SETD1A
– KDM6B
– SETD1B
– BICRA
There is close cooperation with the expertise center at Radboud University Medical Center Nijmegen (Kleefstra-syndrome - RadboudUMC).
Kleefstra syndrome (EHMT1 or 9q34 deletion)
The EHMT1 407 / 5.000 gene was discovered in 2006 as the cause of Kleefstra syndrome, a congenital neurocognitive developmental disorder in which a combination of different conditions can occur. Some examples of this are for example certain typical external characteristics such as a relatively small head, merging eyebrows, obesity, muscle weakness and heart and other congenital abnormalities.
More information can be found on the following websites;
Kleefstra-syndroom – ZeldSamen
KMT2C
Mutations in the KMT2C gene causes a developmental disorder that shows both similarities and differences with Kleefstra syndrome (see above) and is therefore often incorrectly referred to as Kleefstra syndrome type 2.
SETD1A
Mutations in the SETD1A gene can lead to a developmental disorder. Later in life, mutations in this same gene can also increase the risk of schizophrenia.
KDM6B
Also mutations in the KDM6B gene, children generally develop more slowly than normal. Often there is a case of too low muscle tone. Behavioral problems such as ADHD and ASD are also more common in children with a genetic defect in this gene, as are sleep problems. This gene was only described for the first time in 2019 in relation to a neurological developmental delay.
SETD1B
Mutations in SETD1B can also lead to a developmental disorder in children. Often there is a delay in speech-language development (sometimes with loss of skills) and epilepsy. Autism and other behavioral problems are also common, often more severe in boys than in girls.
BICRA
In children with mutations in the BICRA gene we also see a developmental delay, which is particularly evident in the area of speech-language development. Certain typical external characteristics also occur, such as a relatively small head, arched and merging eyebrows, a prominent nose tip and low-set ears.
Chromatinopathies general
Clinical geneticist: Prof. Dr. Tjitske Kleefstra, Dr. Stefan Barakat
Pediatrician Hereditary and Congenital disorders: Dr. Margreth van der Lugt
Researchers: Prof. Dr. Tjitske Kleefstra, Dr. Stefan Barakat, Dr. Dmitrijs Rots
Coordinator: Bianca de Graaf
For SETD1A
Researcher: dr. Femke de Vrij
For SETD1B
Researcher: dr. Kristina Lanko
Click here for general questions via the ENCORE contact form or click here for more information about referral to the Epigenetics Outpatient Clinic.
In order to provide the best possible care to patients with a rare disease, it is essential that knowledge about the disease is gathered worldwide. In order to stimulate the care for rare diseases and the gathering of knowledge, national centers of expertise have been set up.
To learn more about chromatinopathy research at ENCORE, click here
More information can be found on the following websites;