Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000467623 | SCV000563831 | pathogenic | Angelman syndrome; X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome | 2016-10-27 | criteria provided, single submitter | clinical testing | A gross duplication of the genomic region encompassing the full coding sequence of the MECP2 gene has been identified. The boundaries of this event are unknown as the duplication extends beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this duplication is unknown, it may be in tandem or it may be located elsewhere in the genome. Gross duplications of the genomic region encompassing MECP2 have been reported in individuals with developmental delay, intellectual disability, autism, hypotonia, macrocephaly, and/or seizures. These duplications and are known to cause MECP2 duplication syndrome (PMID: 18985075, 16080119, 17172942, 18385275, 20177701). Experimental studies have shown that overexpression of MECP2 in a mouse model recapitulates all the symptoms associated with MECP2 duplication syndrome in humans, including neuronal excitation, seizures, progressive neurological deficiencies and immunological abnormalities (PMID: 15351775, 23220634). Importantly, the expression level of MECP2 in mice correlates with neuronal excitation; knockout of MECP2 results in decreased long-term potentiation (LTP) in neurons while overexpression of MECP2 shows increased LTP (PMID: 17920015), consistent with dosage sensitivity of the MECP2 gene. For these reasons, this variant has been classified as Pathogenic. |