CHAMP1-associated intellectual disability syndrome

CHAMP1-related neurodevelopmental disorder is an ultra-rare genetic disorder caused by changes to the CHAMP1 gene.^[3] The condition is primarily characterized by developmental delay, varying degrees of intellectual disability, and significant speech and language impairment.^[4] Other common features include low muscle tone (hypotonia), feeding difficulties, atypical behaviours, and distinctive facial features.^[5]

Individuals with a CHAMP1-related disorder can have a wide range of clinical features, and not every person will have all possible symptoms.

• Intellectual and Motor Skills: Developmental delay is a universal feature. Most children learn to walk independently, but typically after the age of two, with an average age of 26 months.^[6] All individuals have some degree of intellectual disability, ranging from mild to severe.^[1]
• Speech and Language: Severe speech impairment is a core feature. Many individuals are non-verbal or minimally verbal, although receptive language (understanding) is often stronger than expressive language (speaking). For those who develop speech, first words are achieved late, around 3.5 years on average.^[7] Augmentative and alternative communication (AAC) methods are often vital for communication.
• Behaviour: Many children are described as having a happy and friendly demeanour. However, this often co-exists with challenges such as ADHD (approx. 60%), autism spectrum disorder or autistic traits (approx. 33%), and anxiety (over 70%).^[6][7]

• Facial Features: Characteristic, though sometimes subtle, facial features can include a thin or tented upper lip, a short philtrum, a wide nasal bridge, low-set ears, and an open mouth posture.^[5]
• Muscle Tone and Joints: Hypotonia (low muscle tone) and joint hypermobility are very common.^[1]
• Feeding and Gastrointestinal: Feeding difficulties are common in infancy. Gastroesophageal reflux disease (GERD) and constipation are also frequent concerns.^[7][8]
• Neurological: Seizures occur in approximately 21% of individuals.^[7][8] Structural brain anomalies, such as a thin corpus callosum, are seen in over a third of individuals.^[8]
• Vision: Eye and vision problems are common, including strabismus (squint), refractive errors (hyperopia, myopia), and nystagmus.^[1]

The disorder is caused by pathogenic variants (mutations) or deletions of the CHAMP1 gene, which is located on the long (q) arm of chromosome 13 at position 34.^[3] The condition is autosomal dominant, meaning a change in only one of the two copies of the gene is sufficient to cause the disorder. In almost all known cases, the genetic change is de novo, meaning it occurred spontaneously and was not inherited from a parent.^[4]

The CHAMP1 gene provides instructions for making the CHAMP1 protein, which has several critical roles in the body's cells.

• Cell Division (Mitosis): The protein's primary role is to ensure chromosomes are properly aligned and separated when cells divide, a process critical for development.^[9]
• Neuronal Development: The protein is critical for the maturation and migration of neurons. An altered protein can impair brain development, contributing to intellectual disability.^[10]
• DNA Repair: The CHAMP1 protein also helps repair double-strand breaks in DNA, maintaining the integrity of the genome.^[11]

Different types of genetic changes can affect the CHAMP1 protein in different ways, which may contribute to the variability in symptoms.

• Gene Deletions: The entire CHAMP1 gene is missing on one chromosome, leading to Haploinsufficiency. Individuals with deletions may have milder symptoms.^[12]
• Loss-of-Function (LOF) Variants: These are typically nonsense or frameshift variants that result in a shortened protein. This shortened protein can interfere with the normal protein, a mechanism known as a dominant-negative effect.^[13]
• Gain-of-Function (GOF) Variants: These are typically missense variants that result in an altered protein with a new or enhanced function. These variants are rare.^[14]

Diagnosis is confirmed through genetic testing. Whole exome sequencing (WES) or whole genome sequencing (WGS) are used to identify variants within the gene sequence, while a chromosome microarray analysis (CMA) is often used to detect deletions of the entire gene.^[3]

There is no cure for CHAMP1-related disorder, but supportive therapies can help manage symptoms and improve quality of life. Management typically involves a multidisciplinary team and may include:^[1]

• Physiotherapy to address low muscle tone and gross motor delays.
• Occupational therapy to develop fine motor skills, daily living skills, and manage sensory sensitivities.
• Speech therapy, with a strong focus on AAC methods for individuals who are non-verbal.
• Behavioural therapy to manage features of ADHD, autism, and anxiety.
• Medical management for associated issues such as seizures, GERD, constipation, and vision problems.

CHAMP1-related disorder is considered ultra-rare. As of 2025, fewer than 250 individuals have been identified worldwide.^[2] The condition was first described in 2015, and it is believed to be underdiagnosed due to limited awareness and access to comprehensive genetic testing.^[3][15]

Active research is focused on better understanding the function of the CHAMP1 gene and the mechanisms of the disorder. Patient organizations, such as the CHAMP1 Research Foundation, play a key role in accelerating this work by funding studies and maintaining patient registries. Future therapeutic strategies under investigation include drug repositioning and genetic therapies, such as antisense oligonucleotides (ASOs), although these are still in the early stages of research.

There are two main non-profit organizations offering support for those affected by CHAMP1-related disorders:

• CHAMP1 UK
• The CHAMP1 Research Foundation