MECP2 duplication syndrome

MECP2 duplication syndrome predominantly affects males and typically manifests in early infancy. The cardinal clinical features include moderate-to-severe intellectual disability, developmental delay, hypotonia, epilepsy, recurrent respiratory infections, gastrointestinal dysfunction, autistic traits, and dysmorphic features. Most female carriers of MECP2 duplications are clinically unaffected due to favourable skewing of X-chromosome inactivation. However, a subset may exhibit neuropsychiatric manifestations, learning difficulties, endocrine or autoimmune disorders, and traits associated with the broad autism phenotype. The first systematic study of female carriers also reported high rates of anxiety, compulsive behaviours, and reproductive abnormalities, despite nearly complete inactivation of the duplication-bearing X chromosome in most individuals.

The estimated birth prevalence is 1 in 150,000 live births.

MECP2 duplication syndrome (MRXSL) is characterised by considerable genomic heterogeneity, with nonrecurrent copy number gains varying in size, gene content, and structural complexity. Despite this variability, all pathogenic rearrangements share a minimal critical region containing MECP2 and IRAK1. Complex genomic rearrangements are common. Large cohort studies have shown that increasing MECP2 copy number, particularly in the context of more complex rearrangements such as triplications, is associated with greater clinical severity. These findings support a central role of MECP2 dosage in disease pathogenesis, while also suggesting that CNV structure contributes to phenotypic variability.

MECP2 duplication syndrome follows X-linked inheritance and affects mainly males. In most affected males the duplication is inherited from a heterozygous mother, who is typically unaffected because of extreme skewing of X-chromosome inactivation towards the normal X. Each son of a carrier mother has a 50% risk of inheriting the duplication and being affected, while each daughter has a 50% risk of being a heterozygous carrier. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The clinical phenotype is non-distinctive and overlaps with other syndromic X-linked intellectual disability disorders, so molecular confirmation is needed to establish the diagnosis. Diagnosis is established by molecular genetic testing demonstrating copy number gains involving MECP2 at Xq28. MECP2-associated rearrangements exhibit considerable heterogeneity with respect to size and genomic architecture, including duplications and triplications. While MECP2 expression appears to be a major determinant of clinical outcome, the structure of the genomic rearrangement may further modulate disease severity.

Main differential diagnoses include:

• Int22h1/int22h2-mediated Xq28 duplication syndrome: 0.5-Mb telomeric duplication that can encompass MECP2
• Syndromic (X-linked) intellectual developmental disorders

: caused by loss-of-function MECP2 variants and predominantly affecting females.

• Genetic testing supports establishing the diagnosis by identifying the underlying MECP2 duplication, clarifying the genetic aetiology of a non-distinctive phenotype and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management of neurological, respiratory, gastrointestinal, and developmental aspects, which the treating physicians decide together with the family of the affected individual.
• A known familial duplication supports predictive testing of at-risk relatives, in particular potential carrier females, so they can clarify their personal and reproductive risk and access counselling where indicated.