Molecular characterization of Spanish patients with MECP2 duplication syndrome

Abstract

MECP2 duplication syndrome (MDS) is an X‐linked neurodevelopmental disorder characterized by a severe to profound intellectual disability, early onset hypotonia and diverse psycho‐motor and behavioural features. To date, fewer than 200 cases have been published. We report the clinical and molecular characterization of a Spanish MDS cohort that included 19 boys and 2 girls. Clinical suspicions were confirmed by array comparative genomic hybridization and multiplex ligation‐dependent probe amplification (MLPA). Using, a custom in‐house MLPA assay, we performed a thorough study of the minimal duplicated region, from which we concluded a complete duplication of both MECP2 and IRAK1 was necessary for a correct MDS diagnosis, as patients with partial MECP2 duplications lacked some typical clinical traits present in other MDS patients. In addition, the duplication location may be related to phenotypic severity. This observation may provide a new approach for genotype‐phenotype correlations, and thus more personalized genetic counselling.

Unraveling Molecular Pathways Altered in MeCP2-Related Syndromes, in the Search for New Potential Avenues for Therapy

“…IRAK1 is a signaling kinase of the NF-κB pathway, also upregulated in MeCP2-/y mice. IRAK1 gene is adjacent to MECP2 and both are duplicated in all patients affected by MDS [6,94]. In whole blood, IRAK1 expression showed age-dependent changes in RTT, from lower in young patients than in controls, to higher in older patients than in controls.…”

MECP2-Related Disorders in Males

“…Duplications can be located at different genomic positions. They have been reported in tandem in the same Xq28 region, translocated to the Xp arm, or even outside the X chromosome [47,87,92,123]. Cases of MECP2 triplications have also been described in males [57,68,82,84,93,104].…”

“…The core phenotype of MDS patients includes hypotonia, developmental delay (DD), mostly moderate-severe intellectual disability, autistic features, epilepsy, progressive lower extremity spasticity, poor speech development, recurrent infections, and gastrointestinal problems. Descriptions of individual cases and, specially, of large cohorts have helped us better understand the main and constant symptoms of MDS and expand its phenotype [53,102,109,113,116,119,121,123,129,130,132]. Even so, there are no publications focused on knowing the natural history of this disorder.…”

“…Unfortunately, more than half will possess drug-resistant epilepsy [116]. A decreased pain sensitivity has been found in these children as well [116,123].…”

“…Duplications can be inherited from mothers to their children and the location and gene content is mainly maintained. However, detailed studies of the duplications between different families have revealed that MDS duplications are non-recurrent, as each rearrangement is of a different size and has different breakpoints [62,68,72,82,97,123]. Moreover, Yi et al, found that the transmission of the duplication is not always stable and can increase or decrease in size when passed from mothers to children [105].…”