How Do SETBP1 Gene Changes Affect Child Development and Behavior?

What you need to know

• Changes in the SETBP1 gene can cause two related disorders: SETBP1 haploinsufficiency disorder (SETBP1-HD) and SETBP1-related disorders (SETBP1-RD).
• Both disorders are characterized by intellectual disability, speech and language delays, attention problems, and features of autism spectrum disorder.
• While there are many similarities, some differences exist between the two disorders, particularly in physical health issues.
• Understanding these disorders is crucial for accurate diagnosis, proper medical care, and developing targeted treatments.

What is SETBP1 and how can it affect development?

SETBP1 is a gene that plays an important role in brain development. It helps control how other genes are turned on and off, which is crucial for the proper formation and function of the brain. When there are changes (mutations) in the SETBP1 gene, it can lead to neurodevelopmental disorders.

There are three main types of disorders associated with SETBP1 gene changes:

1. Schinzel-Giedion Syndrome (SGS): A rare and severe condition caused by specific mutations in the SETBP1 gene.
2. SETBP1 haploinsufficiency disorder (SETBP1-HD): Caused by mutations that reduce the amount of functional SETBP1 protein.
3. SETBP1-related disorders (SETBP1-RD): Caused by mutations that change how the SETBP1 protein works, rather than reducing its amount.

This study focused on comparing SETBP1-HD and SETBP1-RD to better understand their similarities and differences.

How was the study conducted?

The researchers collected data from 34 individuals with SETBP1-HD or SETBP1-RD through the Simons Searchlight program, which studies rare genetic neurodevelopmental disorders. They gathered information from medical history interviews and standardized assessments of adaptive functioning, behavior, and social skills.

What are the main features of SETBP1-HD and SETBP1-RD?

Both SETBP1-HD and SETBP1-RD share several common characteristics:

1. Intellectual disability and developmental delays
2. Speech and language impairments
3. Attention problems and hyperactivity
4. Features of autism spectrum disorder
5. Hypotonia (low muscle tone)
6. Sleep issues
7. Vision problems
8. Gastrointestinal problems

One interesting finding was that individuals with both disorders showed a high pain tolerance, which hadn’t been reported before.

How do SETBP1-HD and SETBP1-RD differ?

While there are many similarities, the study found some differences between the two disorders:

1. Heart issues: More common in SETBP1-RD
2. Orthopedic problems: More frequent in SETBP1-RD
3. Bowel control difficulties: More prevalent in SETBP1-RD
4. Somatic issues (physical symptoms): Higher risk in SETBP1-RD
5. Neonatal feeding difficulties: More common in SETBP1-HD
6. Febrile seizures: Higher rates in SETBP1-HD

What did the study reveal about cognitive and adaptive functioning?

The researchers used a test called the Vineland Adaptive Behavior Scales (VABS-3) to assess how well individuals could function in daily life. For those with SETBP1-HD:

• Communication was the most impaired area
• Social skills were relatively stronger
• Motor skills and daily living skills showed moderate impairment

Overall adaptive functioning for both SETBP1-HD and SETBP1-RD fell in the borderline to mild impairment range.

What about behavior and social skills?

The study used several assessments to look at behavior and social skills:

1. Child Behavior Checklist (CBCL):

   • Both groups showed elevated attention problems
   • SETBP1-HD had more issues with social problems and thought problems
   • SETBP1-RD showed more somatic complaints

2. Social Responsiveness Scale (SRS-2):

   • Both groups showed moderate difficulties in social communication and interaction
   • Restricted and repetitive behaviors were a challenge for both groups
   • Social motivation was a relative strength, especially for the SETBP1-HD group

3. Social Communication Questionnaire (SCQ):

   • About half of the SETBP1-HD group and all of the SETBP1-RD group scored in a range suggesting possible autism spectrum disorder

What about sleep issues?

Sleep problems were common in both groups:

• 64% of SETBP1-HD individuals met criteria for potential sleep disorders
• 67% of SETBP1-RD individuals had significant sleep disturbances
• Night wakings and daytime sleepiness were particular issues for the SETBP1-HD group
• The SETBP1-RD group had more problems with sleep duration and bedtime resistance

Many families reported using melatonin to help with sleep problems.

What treatments are currently used?

While there are no treatments specifically for SETBP1-HD or SETBP1-RD, the study found that many individuals were using various medications to manage symptoms:

• ADHD medications (stimulants and non-stimulants) were commonly used in both groups
• Gastrointestinal medications were frequently reported
• Some individuals used anti-anxiety medications or anti-seizure drugs
• Fish oil supplements were popular, with many families reporting improvements

Why is this study important?

This research provides the most comprehensive description to date of the clinical and behavioral features of SETBP1-HD and SETBP1-RD. Understanding these disorders is crucial for several reasons:

1. Accurate diagnosis: Knowing the typical features of these disorders can help doctors identify them more quickly and accurately.
2. Improved medical care: Understanding the associated health issues allows for better monitoring and management of potential problems.
3. Treatment development: Detailed knowledge of these disorders is essential for developing targeted treatments in the future.
4. Family support: Families affected by these rare disorders can better understand what to expect and how to support their loved ones.

Conclusions

• SETBP1-HD and SETBP1-RD are rare neurodevelopmental disorders with overlapping features, including intellectual disability, speech delays, and attention problems.
• While similar in many ways, there are some differences in physical health risks between the two disorders.
• Social motivation appears to be a relative strength for individuals with these disorders, while repetitive behaviors and communication difficulties are common challenges.
• This study provides valuable information for improving diagnosis, medical care, and future treatment development for individuals with SETBP1-related disorders.