Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MECP2 : Rett syndrome

HGNC:6990 | MONDO_0010726
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Rett Angelman EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Amir RE et al. 1999 Oct (PMID:10508514); De Bona C et al. 2000 May (PMID:10854091);
Proband with predicted or proven null variant 1.5 0-2 10 1.5 1.5
Amir RE et al. 1999 Oct (PMID:10508514);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Amir RE et al. 1999 Oct (PMID:10508514);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 4
Chen RZ et al. 2001 Mar (PMID:11242118); McGraw CM et al. 2011 Jul 8 (PMID:21636743);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Guy J et al. 2007 Feb 23 (PMID:17289941);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 4 16 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
MECP2 was discovered as the causative gene of Rett syndrome in 1999, and since then over 4,600 MECP2 variants have been identified (Wan et al. 1999, Bienvenu et al. 2000, Krishnaraj et al. 2017). MECP2-associated Rett syndrome is an X-linked dominant disease affecting primarily females. Rett syndrome is characterized by normal development during the first 6-18 months of life followed by a phase of rapid regression in language and motor skills followed by long-term stability. Other features include stereotypic hand movements, fits of screaming and crying, autistic features, panic-like attacks, bruxism, apnea, gait ataxia, tremors, seizures, and acquired microcephaly. The majority of MECP2 variants arise de novo, however some instances of maternal germline mosaicism have been described (Amir et al. 1999, Venancio et al. 2007). The majority of de novo variants are paternal in origin (Zhang 2012), and in such families only females would be affected. However, some males hemizygous for MECP2 variants are viable and have severe neonatal encephalopathy and intellectual disability. Many mouse models of MECP2-deficiency have phenotypic features consistent with Rett syndrome (Chen et al. 2001, Guy et al. 2001, Shahbazian et al. 2002, Guy et al. 2007, McGraw et al. 2011). In summary, MECP2 is definitively associated with Rett syndrome in an X-linked dominant manner. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More information can be found at GeneReviews (