Last updated:
10/25/2023
Years published: 2023
NORD gratefully acknowledges Alexandra Roston, MD, MSc, Resident in Medical Genetics, University of British Columbia and BC Cancer Agency Research Institute and William T. Gibson, MD, PhD, Senior Clinician Scientist, UBC and British Columbia Children’s Hospital Research Institute, for the preparation of this report.
SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is thought to be caused by disease-causing changes (pathogenic variants) in the SETD1B gene. Affected patients may have developmental delays or intellectual disability, seizures, autism spectrum disorder or autism-like behaviors and other behavioral challenges. Speech disorders, seizures and autism-like features are some of the most common features observed in patients with SETD1B-NDD.
There is no curative treatment for SETD1B-NDD. Rather, the goals of management are to support young patients in their development and communication skills and ensure families have adequate social supports. In addition, feeding difficulties, seizures and other medical concerns may need to be managed as they arise. In general, when a patient is diagnosed with SETD1B-NDD, it is recommended that at minimum, patients be referred to a geneticist or genetic counselor, neurologist and developmental pediatrician.
• Developmental delay (including speech delays/disorders)
• Intellectual disability (ID)
• Seizures (especially seizures that are difficult to treat)
• Autism-spectrum disorder or autism-like behaviours
• Other behavioral concerns (hyperactivity, aggression, anxiety, sleep disorders)
Developmental delay and Intellectual Disability
Many individuals with SETD1B-NDD have developmental delays. One of the most common affected areas is speech, with speech delays and language disorders reported in most patients. There is a range in severity of delay; some patients show speech delay but catch up later, though some show severe speech impairment. Some patients are non-verbal, or only speak single words at the time of their last reported assessment. Other developmental delays can include delays in gross motor skills, like rolling from back-to-front or front-to-back as an infant, sitting independently, walking or running. There are very few detailed reports on fine motor skills (such as picking up food or using a pencil) among individuals with SETD1B-NDD. A small number of patients have also had developmental regression, or loss of developmental milestones; in these patients, speech was affected, and patients lost previously acquired verbal skills or vocabulary.
When diagnosed with intellectual disability (ID), most individuals seem to be affected to a mild or moderate degree. At least two patients have been reported to have severe ID. However, at least two patients reported in the medical literature had typical development (they were meeting developmental milestones) at the time of their assessment.
Seizures
Seizures are common in patients with SETD1B-NDD, and often present at a young age. Many different types of seizures have been reported, but in most reports, seizures occur daily and change in character as children get older. Seizures may worsen over time, or be difficult to treat, requiring trials of different medications. No universal anti-seizure treatment has been reported to be effective in all individuals.
Other Neurologic Symptoms
A small number of individuals have been reported to have feeding difficulties early in childhood. Some patients have also been reported to have low muscle tone (hypotonia) and one adult had a small head circumference (microcephaly).
Behavioral Differences
Most patients described in the literature have either autism spectrum disorder or autistic features without a formal diagnosis. Other behavioral concerns reported include hyperactivity, aggression, anxiety, sleep disturbance and more rarely, obsessive-compulsive behavior.
Other
Some patients also had abnormalities on brain MRI (a type of head imaging), subtle facial features different from other family members, eye abnormalities or other medical conditions (for example, one patient had a congenital heart abnormality and another was born with abnormal kidneys). However, there was no recognizable pattern of facial features or common diagnosis among the reported patients.
Variants in the SETD1B gene have been reported in the tissue found in cancerous tumours; laboratory studies have also shown that SETD1B variants may play a role in endometrial cancer and some types of blood cancer. However, in these cases, the pathogenic variants occur in the tumor tissues only (this is called a somatic mutation) as opposed to in every cell in the body (germline mutation; this is the process that occurs in SETD1B-NDD). To date, there are no reports of patients with germline SETD1B variants (e.g., patients with SETD1B-NDD) who had cancers diagnosed in childhood. Among the patients reported thus far, only one individual has been reported to have a malignancy, and this was a bowel cancer diagnosed at age 30 years.
SETD1B-NDD is caused by likely pathogenic or pathogenic variants (disease-causing changes) in the SETD1B (SET domain-containing protein 1B) gene. This gene produces a protein with the same name (SETD1B) which helps package and organize the DNA strand. The SETD1B protein helps with DNA unpacking by adding methyl groups to the amino acid “tail” of a specialized protein, called a histone (this chemical reaction is known as “methylation”). By adding the methyl group to the histone tail, the SETD1B protein directs the histone to package DNA into more loosely coiled strands (instead of tighter, more closed strands). “Loose” DNA is generally more accessible to the cell’s “transcriptional machinery”, and therefore genes with SETD1B-derived markings near their transcriptional start sites are more likely to be expressed. This balance of tightly packaged or looser DNA is a very important step in regulating how DNA is expressed in the body, especially inside neurons.
Because the SETD1B protein has a role in this process, researchers believe that non-functioning SETD1B leads to mistakes in DNA packaging. These mistakes would then lead to the incorrect repression of genes located within the areas that have been packaged incorrectly.
Most healthy people have two working copies of the SETD1B gene; one copy is inherited from the biological mother, and the other is inherited from the biological father. SETD1B-NDD occurs when at least one of these copies has a mistake in the genetic code (also called a likely pathogenic or pathogenic variant) or has been deleted. This situation, in which one non-working copy is enough to cause a disease, is known as a “dominant” effect. Therefore, SETD1B-NDD is an autosomal dominant condition. The risk of a person (male or female) passing on a dominant pathogenic variant is 50% with each pregnancy.
To date, many of the pathogenic variants identified in patients with SETD1B-NDD are unique. Although they usually arise for the first time in the affected patient (as opposed to being inherited from a parent), there have been some reports of children and parents sharing the same pathogenic variant.
The incidence and prevalence of SETD1B-NDD is unknown, but it seems to be very rare. As of 2023, about 38 individuals have been reported in the medical literature with this disorder. Most patients with SETD1B-NDD are diagnosed in early childhood, once genetic testing is complete. Because this disorder has some features common in other conditions (see below), it is only diagnosed after a likely pathogenic or pathogenic variant in SETD1B has been identified on genetic testing.
Diagnosis is usually made based on: (1) a likely pathogenic or pathogenic variant in the SETD1B gene, identified on molecular genetic testing, plus (2) some combination of the features described above.
Because the findings of SETD1B-NDD are common and can be present in other conditions, single-gene sequencing for SETD1B is not recommended. Rather, most patients are diagnosed following exome sequencing (genetic testing of a large portion of the DNA) or by panel testing of symptom-specific genes (for example, on an epilepsy or autism gene panel).
There is no cure for SETD1B-NDD and there are no medications that directly target the molecular cause of this disorder. Rather, once diagnosed, the goal is to support the patient’s neurodevelopment and manage ongoing medical issues as best as possible.
Following diagnosis, specialist evaluations should be considered. Patients may also require ongoing evaluation and reassessment periodically throughout childhood and their adult lives.
In general, because patients with SETD1B-NDD often have difficulty expressing themselves, they may not be able to communicate pain or discomfort. For this reason, there should be a low threshold for subspecialty referral or physician assessment.
Development
A full developmental assessment by a developmental pediatrician is recommended. Assessment should include motor and cognitive skills as well as speech and language evaluation. Formal autism assessment should also be considered.
In general, younger patients (0-3 years) should be referred to early intervention programs as soon as possible to help them gain developmental milestones (e.g., walking, feeding) in a supportive environment, and ease the transition to the school system. In the United States, there are federally funded early intervention programs in every state. For children aged 3-5 years, developmental supports should continue, and preschool/school systems should be made aware of the child’s individual needs through an individualized education plan (IEP) or other documentation.
Children will likely benefit from periodic assessments by a developmental pediatrician throughout childhood, as their developmental needs may change. Additionally, given the frequency of language disorders, children should be provided with assistive communicative devices and language supports as needed.
In the United States, there are several supports to consider, including an IEP (individualized education plan), a 504 plan (prohibits discrimination based on disability), Developmental Disabilities Administration (DDA) enrolment and supplemental security income (SSI). It is recommended that families speak with care providers about these supports or find out more about supports available in their region.
Neurologic Symptoms
A full assessment by a neurologist is recommended. The neurologist may suggest additional tests such as an EEG (a test to assess for seizures) or head imaging. Seizures are a common feature of SETD1B-NDD and may be difficult to treat. Patients may require frequent follow up with their neurologist. Currently, there are no published recommendations regarding specific seizure therapies and their efficacy in SETD1B-NDD. Neurological regression should prompt assessment by a neurologist to identify any treatable causes of regression.
Some patients may also have difficulty with abnormal muscle tone (low tone known as hypotonia, or high tone, known as spasticity). They may need further support with physiotherapy, occupational therapy or physiatry (physical medicine). Further discussion of these issues is below, under “Musculoskeletal Concerns.”
Mental Health/Behavior
Assessment by neuropsychiatry or a psychiatrist with experience in developmental disorders is recommended. Evaluation may include screening for behavioral concerns, sleep disturbances, ADHD, anxiety or (as mentioned above) autism spectrum disorder. New-onset psychiatric symptoms should prompt assessment by a neurologist to identify any treatable causes of regression.
Musculoskeletal Concerns
Depending on the individual’s presentation, evaluation by orthopedics, physiatry or physiotherapy/occupational therapy may be indicated. Specialist assessment may include evaluation for orthopedic abnormalities, adaptive devices or PT/OT support for improving motor skills.
Feeding/Gastrointestinal Issues
Evaluation by gastroenterology or a feeding team may be indicated to support feeding and nutritional status. For some patients, swallowing studies or investigations to assess the risk of choking (aspiration) may also be recommended.
Because good nutritional support is critical to health and child development, the threshold for assessment should be low.
Vision and Hearing
Evaluation by an eye specialist and hearing assessments are recommended, as individuals may not be able to communicate difficulties with vision or hearing. Depending on findings, further subspecialty referral may be recommended.
Sleep
Sleep studies or other evaluations may be indicated in patients with sleep disturbances or other symptoms.
Genetic Counseling
Genetic counselling is recommended, to explain test results and next steps for family members. A genetic counselor may also be able to assist with decision-making or answer specific questions. Disease-causing variants are typically de novo mutations, not inherited from affected parents. Nevertheless, the biological mother and/or the biological father may wish to be tested for their child’s variant, since some parents are thought to have the variant present in some other cells and not others (“mosaicism”). When a disease-causing variant is confirmed to be de novo in a patient born to unaffected parents, future siblings of that patient are thought to be at a risk of approximately 1% of inheriting the same variant from the father’s sperm or mother’s egg. Each child of a person with SETD1B-NDD has a 50% risk of inheriting the non-working copy of the gene. The risk is the same for males and females.
Family Support
Families may require referrals to family support services or home nursing teams. Social work involvement and caregiver support should be considered.
There are currently no clinical trials being conducted for SETD1B-associated neurodevelopmental disorder.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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INTERNET
Roston A, Gibson W. SETD1B-Related Neurodevelopmental Disorder. 2022 Sep 29. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK584549/ Accessed Oct 23, 2023.
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