Understanding Intellectual Developmental Disorder (MRD23) and the Role of the SETD5 Gene

1. What Is Intellectual Developmental Disorder (IDD)?

Intellectual Developmental Disorder (IDD) is a neurodevelopmental condition marked by:

Significant limitations in intellectual functioning – including reasoning, problem-solving, learning, and abstract thinking.
Deficits in adaptive behavior – such as communication, self-care, social interaction, and independent living.
Onset before age 18 – symptoms are typically recognized during early childhood.

These limitations can range from mild to severe and affect an individual's ability to lead an independent life.

Diagnostic Criteria:

IDD is defined by standard criteria such as those found in the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition):

2. What Is MRD23?

MRD23 stands for:

Mental Retardation, Autosomal Dominant 23

It is a rare, genetically defined form of IDD that results from mutations in the SETD5 gene. The condition is classified as autosomal dominant, meaning that just one copy of the mutated gene (from one parent or from a de novo mutation) is sufficient to cause the disorder.

Key Features of MRD23:

Global developmental delay (GDD)
Mild to moderate intellectual disability
Delayed speech and language development
Motor coordination difficulties
Behavioral similarities to ASD or ADHD
Variable physical features (often subtle or non-specific)

MRD23 is cataloged in the Online Mendelian Inheritance in Man (OMIM) database:

OMIM Entry: MRD23 - #615761

3. What Is the SETD5 Gene?

SETD5 (SET domain-containing protein 5) is a gene located on chromosome 3 (3p25.3). It encodes a protein that plays a critical role in:

Epigenetic regulation:

SETD5 helps control gene expression — turning genes on or off — especially during early development.

Neurodevelopment:

It is especially active in the developing brain and is important for the proper formation and function of neurons (brain cells).

A properly functioning SETD5 gene ensures that other essential developmental genes are expressed at the right times and in the right amounts.

Further reading: Genetics Home Reference: SETD5 gene

4. What Is a "Pathogenic Variant" in SETD5?

A pathogenic variant refers to a disease-causing mutation in the SETD5 gene. This type of mutation disrupts the normal function of the gene, affecting its ability to regulate other genes during brain development.

Mutation Types May Include:

Loss-of-function mutations
Frameshift or nonsense mutations
Deletions involving part or all of the gene

These mutations lead to impaired cognitive, behavioral, and developmental functions.

Inheritance Patterns:

De novo mutation (most common): The mutation appears spontaneously and is not inherited from either parent.
Inherited mutation (rare): In some cases, the mutation may be passed from a parent, even if the parent shows no symptoms (due to mosaicism or reduced penetrance).

Reference:

Deciphering Developmental Disorders Study. (2015). Large-scale discovery of novel genetic causes of developmental disorders

5. Clinical Implications of MRD23 (SETD5-related IDD)

People with MRD23 may present with a range of symptoms and characteristics, including:

Cognitive & Developmental:

Intellectual disability (mild to moderate)
Speech and language delays
Learning disabilities
Global developmental delay (motor, cognitive, language)

Behavioral:

Features of autism spectrum disorder (ASD): limited eye contact, social withdrawal, repetitive behaviors
Signs of attention-deficit/hyperactivity disorder (ADHD)

Neurological:

Hypotonia (low muscle tone)
Seizures (in some cases)
Structural brain differences (identified via MRI in some individuals)

Physical Features:

Subtle facial differences (e.g., broad forehead, flat nasal bridge)
Variable; not all individuals show physical dysmorphisms

Each case is unique — some individuals may have only mild symptoms, while others have more complex needs.

6. Diagnosis and Management

Diagnosis

Diagnosis typically involves:

Developmental assessment
Genetic testing such as:
- Whole exome sequencing (WES)
- Chromosomal microarray analysis (CMA)
- Targeted gene panels for intellectual disability or neurodevelopmental disorders

Testing can identify mutations in the SETD5 gene and confirm the diagnosis of MRD23.

Example clinical genetic testing resource: GeneDx – SETD5 Testing

Management

There is no cure for MRD23, but supportive therapies can significantly improve outcomes:

🔹 Early Intervention Programs:

Special education plans
Developmental support services

🔹 Therapies:

Speech and language therapy
Occupational therapy
Physical therapy

🔹 Behavioral and Psychological Support:

Applied Behavior Analysis (ABA)
Counseling and social skills training

🔹 Medical Management:

Anti-epileptic drugs (if seizures occur)
Regular follow-ups with neurology, genetics, and developmental pediatrics

🔹 Genetic Counseling:

Essential for parents to understand recurrence risks
Prenatal testing may be considered in future pregnancies

Summary

Feature	Details
Condition	MRD23 – Intellectual Developmental Disorder caused by a SETD5 mutation
Gene involved	SETD5
Inheritance	Autosomal dominant (often de novo)
Key symptoms	Developmental delays, intellectual disability, speech issues, possible ASD/ADHD traits
Diagnosis	Genetic testing (e.g., WES)
Treatment	Supportive – no cure, but early intervention and therapy can greatly help
Prognosis	Variable; with support, many individuals improve quality of life and communication skills

References: Unfortunately, some links are no longer available.

Health conditions caused by changes in the SETD5 gene
https://www.genetics.edu.au/SitePages/SETD5.aspx

SETD5 Gene - SET Domain Containing 5
https://www.genecards.org/cgi-bin/carddisp.pl?gene=SETD5&utm_source=chatgpt.com

OMIM: MRD23 – Mental Retardation, Autosomal Dominant 23
https://www.omim.org/entry/615761

Deciphering Developmental Disorders Study (2015)
https://www.nature.com/articles/nature14135

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