Systematic Review of Females With Intellectual Disability and MECP2 Duplication.

Abstract

MECP2 Duplication Syndrome (MDS) is a rare, X-linked neurodevelopmental disorder typically affecting males. Females with MDS have been reported and are compiled here. We conducted a systematic review (PROSPERO CRD420250652426) of PubMed, EMBASE, and Google Scholar extracting individual participant data. Inclusion required confirmed full MECP2 gene duplication and evidence of ID (IQ < 75 or significant deficits in adaptive functioning). Affected females were compared with a published male MDS dataset, stratified by genetic variant. From 590 full-texts, 41 unique female records were included. Tandem duplications were most frequent (59%), followed by unbalanced autosomal translocations (32%), other terminal duplications (7.3%), and one triplication. Most tandem duplication females exhibited skewed X-inactivation (14/18 reports) and presented with mild-to-moderate developmental delay, partially retained speech and ambulation (all but one report), and fewer neurological/systemic manifestations relative to male counterparts. Females with unbalanced translocations or other terminal duplications had severe ID, absent speech (5/9 reports), and severe epilepsy (8/16 reports included drug-resistant epilepsy). Features included respiratory infections (12/14), feeding problems (8/11), microcephaly (10/14), and shortened survival. Affected females show genotype-dependent severity: tandem duplications were associated with broader, generally less severe phenotypes and variable epilepsy expression, whereas severe translocation/terminal duplication females may resemble male MDS.