MECP2 – Atypical Rett Syndrome

MECP2 encodes methyl-CpG binding protein 2, a chromatin‐associated transcriptional repressor on Xq28. Atypical Rett syndrome is an X-linked dominant neurodevelopmental disorder characterized by regression of acquired skills, stereotyped hand movements, and variable phenotypes including preserved speech or congenital onset. Pathogenic MECP2 variants disrupt DNA methylation-dependent repression, leading to neuronal dysfunction in girls and rare surviving males with skewed X-inactivation. MECP2 variants are established causes of both classic and atypical Rett presentations, informing molecular diagnostics and genetic counselling.

In a cohort of 110 MECP2‐mutation negative Rett patients, dosage analysis identified large MECP2 deletions in 37.8% of classic and 7.5% (4/53) of atypical cases, demonstrating mutation under-ascertainment by sequencing alone (PMID:16183801). This series provides direct evidence in 4 unrelated atypical Rett probands, supporting a causal role of MECP2 dosage defects in atypical phenotypes.

Beyond large deletions, point mutations and truncating variants are observed across methyl-CpG binding and transcriptional repression domains. A representative allele in atypical cases is c.799C>T (p.Arg267Ter), which abolishes the C-terminal repression domain and predicts loss of function (PMID:16183801). No multi-generational segregation in atypical families has been reported to date.

Functional studies confirm that MECP2 haploinsufficiency underlies Rett pathology. Mecp2-null mice develop progressive motor and cognitive deficits with neuronal atrophy, recapitulating human Rett features, including those seen in atypical variants (PMID:11242118). In vitro assays of methyl-CpG binding domain mutants reveal marked reductions in DNA affinity and transcriptional repression, consistent with a loss-of-function mechanism.

Conflicting evidence arises from a pediatric epilepsy case initially attributed to novel MECP2 variants but ultimately linked to a de novo GNAO1 mutation. Family segregation and exome data refuted MECP2’s role in that atypical presentation, underscoring the importance of comprehensive genetic and clinical correlation (PMID:29961512).

Integration of case-level and experimental data yields a coherent model: MECP2 loss-of-function variants, including large deletions and truncating point mutations, drive atypical Rett syndrome via haploinsufficiency. While evidence in atypical cohorts remains limited, functional concordance and animal models strengthen the gene–disease link. Key take-home: inclusion of quantitative dosage analysis alongside sequencing is critical for accurate molecular diagnosis of atypical Rett syndrome.

References

• Journal of medical genetics • 2006 • Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. PMID:16183801
• Nature genetics • 2001 • Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. PMID:11242118
• Seminars in pediatric neurology • 2018 • Neonatal epileptic encephalopathy caused by de novo GNAO1 mutation misdiagnosed as atypical Rett syndrome: Cautions in interpretation of genomic test results. PMID:29961512

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