9q34 deletion syndrome

Overview

9q34 deletion syndrome, more commonly known as Kleefstra syndrome, is a rare genetic disorder caused by a deletion or mutation affecting the EHMT1 gene located on the long arm of chromosome 9 at position 34. This syndrome is characterized by developmental delay, intellectual disability, distinctive facial features, hypotonia (low muscle tone), and behavioral challenges, including features of autism spectrum disorder (ASD). The condition is named after Dutch geneticist Tjitske Kleefstra, who helped identify the syndrome.

Causes

The syndrome is most often caused by a microdeletion at chromosome 9q34.3, specifically affecting the EHMT1 gene, which plays a crucial role in chromatin modification and regulation of gene expression during brain development. Alternatively, point mutations in the EHMT1 gene can also result in Kleefstra syndrome without a larger chromosomal deletion.

Most cases occur sporadically (de novo) with no family history. However, in rare instances, the deletion or mutation may be inherited in an autosomal dominant pattern.

Symptoms

Clinical features of 9q34 deletion syndrome vary in severity but often include:

• Moderate to severe intellectual disability

• Global developmental delay: Including speech and motor skills

• Hypotonia: Especially noticeable in infancy

• Autism spectrum disorder (ASD) traits: Including limited communication, repetitive behaviors, and sensory sensitivities

• Behavioral issues: Including anxiety, aggression, or sleep disturbances

• Distinctive facial features: Including arched eyebrows, midface retrusion, short philtrum, everted lower lip, and protruding tongue

• Feeding difficulties

• Seizures: In some individuals

• Heart defects: Congenital anomalies such as septal defects (less common)

• Genitourinary anomalies: Including undescended testes or renal malformations

Diagnosis

Diagnosis is based on clinical features and confirmed through genetic testing. Diagnostic steps include:

• Chromosomal microarray (CMA): Detects deletions in the 9q34.3 region

• Targeted gene sequencing: Identifies point mutations in the EHMT1 gene

• FISH (fluorescence in situ hybridization): May confirm deletions when CMA is not available

• Parental testing: Determines if the mutation or deletion is inherited or de novo

Genetic testing is typically pursued in children with unexplained developmental delays and dysmorphic features.

Treatment

There is no cure for 9q34 deletion syndrome, but a multidisciplinary approach can help manage symptoms and maximize developmental potential. Treatment options include:

• Speech, physical, and occupational therapy: Early and ongoing support for communication and motor skills

• Special education: Individualized learning plans and classroom accommodations

• Behavioral therapy: Especially helpful for ASD-related traits or challenging behaviors

• Medical management: For seizures, heart defects, or gastrointestinal issues

• Sleep management: Behavioral or pharmacologic support for sleep disorders

• Genetic counseling: For families to understand the condition and recurrence risk

Prognosis

The prognosis for individuals with 9q34 deletion syndrome depends on the severity of intellectual and medical challenges. While most will have lifelong developmental and cognitive impairments, many children can make significant progress with early intervention. With appropriate therapies, supportive education, and medical care, individuals may achieve varying degrees of independence. Life expectancy is generally normal unless serious congenital anomalies or medical complications are present.