Rett Syndrome
Mutations in MECP2 have been identified in patients with Rett Syndrome, Autism, X-linked mental retardation, females with mild learning disabilities, and males with neonatal encephalopathy.
PrintMutations in MECP2 have been identified in patients with Rett Syndrome, Autism, X-linked mental retardation, females with mild learning disabilities, and males with neonatal encephalopathy.
Rett Syndrome is the only Autism Spectrum Disorder with a known cause. The MECP2 Duplication Syndrome causes infantile hypotonia, seizures, mental retardation, absence of speech, spasticity and recurrent respiratory infections in boys.
MECP2 analysis can detect mutations in 96% of classic Rett Syndrome patients and 58-75% of atypical cases with deletions accounting for 11.9% of mutations. Among atypical Rett Syndrome patients who do not have an MECP2 mutation, 12.9% will have a mutation in the CDKL5 gene. CDKL5 mutations are also associated with severe early onset seizures.
The Ambry SEQUENCE™: Rett Syndrome is our most comprehensive test for typical and atypical Rett Syndrome. This is a three-step reflex testing pathway to detect, in order, MECP2 sequence variants, MECP2 deletions and duplications, and lastly, CDKL5 sequence variants.
The MECP2 AMPLIFIED™ is also a stepwise analysis for MECP2 sequence variants with reflex to MECP2 Deletion/Duplication Analysis. CDKL5 analysis is not part of the testing pathway in MECP2 AMPLIFIED™. Gene Sequence Analysis for MECP2 or CDKL5 and Deletion/Duplication Analysis of MECP2 may also be ordered separately or in any combination.
For information about CDKL5-Related Infantile Spasms, please see the separate CDKL5-Related Infantile Spasms web page and Test Information Sheet.
Analysis of this CDKL5 and MECP2 are also available as part of the X-Linked Intellectual Disabilities SuperPANEL™.
MECP2 mutations have been identified in patients with Rett syndrome, autism, X-linked mental retardation, females with mild learning disabilities, and males with neonatal encephalopathy.1 Rett syndrome is an X-link dominant condition that is a severe, progressive neurologic disorder, and is the only known Autism Spectrum disorder with a known cause. It is characterized by normal birth development followed by rapid regression in intelligence, language and motor skills, autistic features, and development of stereotypic hand movements. There may also be seizures, hyperventilation, apnea, scoliosis, growth retardation and gait dyspraxia.2 The prevalence of Rett syndrome in females is estimated to be 1:8,000,3 but the prevalence of all MECP2-related disorders is unknown. It is possible for males to have Rett syndrome, but most have such severe encephalopathy that they do not live past infancy.1 However, other MECP2 mutations may account for 1.3-1.7% of mental retardation in male patients.4 In addition, duplications in MECP2 can cause infantile hypotonia, seizures, mental retardation, absence of speech, spasticity and recurrent respiratory infections in boys, which is also known as MECP2 Duplication Syndrome.5
The MECP2 gene encodes the MeCP2 protein which is thought to be involved in neuronal development and differentiation,6 gene expression through CpG binding, and as a transcriptional repressor.7 Variability in the phenotype is often seen due to the type of mutation and X-chromosome inactivation.1 The majority of MECP2-related disorders result from a de novo mutation, though inheritance of the disease mutation can occur due to an affected mother with mild symptoms caused by favorably skewed X-inactivation, or a parent with a germ-line mosaicism.8 MECP2 analysis can detect mutations in 96% of classic Rett syndrome patients and 58 - 75% of atypical cases9,10 with deletions accounting for 11.9% of mutations.11 The lack of MECP2 mutations in some clinically defined Rett syndrome cases suggests genetic heterogeneity, with the existence of at least one other locus, CDKL5. Rett syndrome, MECP2 negative Rett, and autism spectrum disorder cases with seizures.12 Out of the population with atypical Rett who do not have an MECP2 mutation, approximately 12.9% will have a mutation in the CDKL5 gene.16
For information about CDKL5-Related Infantile Spasms, please see our separate test information sheet and webpage.
Testing is recommended for those with cognitive impairment13 or symptoms of MECP2-related disorders. Because germ-line mosaicism cannot be excluded, prenatal diagnosis should be offered to those with a family history of a MECP2-related disorder regardless of whether the mutation has been found in a parent.9
Testing for MECP2 mutations has also been recommended by the American College of Medical Genetics as part of their diagnostic evaluation for Autism Spectrum Disorder.1
The Ambry SEQUENCE: Rett Syndrome is our most comprehensive test for typical and atypical Rett. This is a three-step reflex testing pathway to detect, in order, MECP2 sequence variants, MECP2 deletions and duplications, and lastly, CDKL5 sequence variants. If a causative mutation is detected in steps one or two of the SEQUENCE, the remaining steps are cancelled to avoid unnecessary testing and cost.
MECP2 AMPLIFIED is also a stepwise analysis for MECP2 sequence variants with reflex to MECP2 deletion/duplication analysis. CDKL5 analysis is not part of the testing pathway in MECP2 AMPLIFIED.
Gene sequence analysis for MECP2 or CDKL5 and deletion/duplication analysis of MECP2 may also be ordered separately or in any combination. MECP2 deletion/duplication testing can be ordered alone for diagnosis of MECP2 Duplication Syndrome. Specific mutation analysis for individual mutations known to be in the family is also available. In this AMBRY SEQUENCE, full gene sequence analysis of MECP2 is performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 1-4 of the MECP2 gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns. Gross deletion deletion/duplication analysis of MECP2 is performed by MLPA®. Gene sequence analysis of CDKL5 is performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 2-21, plus at least 20 bases in at least one direction into the 5’ and 3’ ends of all the introns.
As described above, the combination of MECP2 gene sequence analysis and deletion/duplication testing identifies mutations in approximately 95% of classic Rett cases 14 and 58-75% of atypical cases9,10 Another 12.9% of patients of patients with atypical Rett and negative MECP2 analysis are positive for CDKL5 sequence mutations (clinical sensitivities).16 The Ambry SEQUENCE: Rett Syndrome identifies approximately 99% of described MECP2 and CDKL5 mutations (analytic sensitivity).
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 μg in TE at 50-100 ng/μl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.
| Test Code | Technique | CPT Codes |
|---|---|---|
| 2020 | MECP2 Gene Sequence Analysis |
83891x1, 83894x9, 83898x8, 83904x16, 83909x16, 83912x1 |
| 2022 | MECP2 Deletion / Duplication |
83891x1, 83894x1, 83900x1, 83901x12, 83909x1, 83912x1 |
| 2026 | MECP2 Gene Sequence and Deletion / Duplication |
83891x1, 83894x9, 83898x8, 83900x1, 83901x12, 83904x16, 83909x17, 83912x2 |
| 2040 | CDKL5 Gene Sequence Analysis | 83891x1, 83894x23, 83898x22, 83904x43, 83909x43, 83912x1 |
| 2028 | Rett Syndrome Steps 1-3 Concurrent (CDKL5 and MECP2, With MECP2 Deletion / Duplication) | 83891x1, 83894x32, 83898x30, 83900x1, 83901x12, 83904x59, 83909x60, 83912x3 |
| 8200 | Rett Syndrome Steps 1-3. (MECP2 Sequence Reflex Option to MECP2 Deletion / Duplication Reflex Option to CDKL5 Sequence) | 83891x1, 83894x32, 83898x30, 83900x1, 83901x12, 83904x59, 83909x60, 83912x3 |
| Technique | Days |
|---|---|
MECP2 Gene Sequence Analysis |
10-21 |
MECP2 Deletion / Duplication |
7-14 |
MECP2 Gene Sequence and Deletion / Duplication |
10-21 |
| CDKL5 Gene Sequence Analysis | 10-21 |
| Rett Syndrome Steps 1-3 Concurrent (CDKL5 and MECP2, With MECP2 Deletion / Duplication) | 10-21 |
| Rett Syndrome Steps 1-3. (MECP2 Sequence Reflex Option to MECP2 Deletion / Duplication Reflex Option to CDKL5 Sequence) | 10-42 |
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13 Percy AK. J Child Neurol. 2008;23:543-549.
14 Schaefer GB et al. Genet Med. 2008:10(4);301-305.
15 Schollen E, Smeets E, Deflem E, et al. Hum Mut. 2003;22:116-20.
16 Bahi-Buisson N, Nectoux, J, Rosas-Vargas, H, et al. Brain. 2008; 131, 2647-2661.