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Molecular Genetics Laboratory

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Atypical Rett Syndrome PANEL or X-linked Infantile Spasms PANEL (ARX, CDKL5, MecP2 Sequence and Del-Dup Analysis)

  • LIS Mnemonic: MBATYPRETT

    Collect

    Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is also acceptable.

    Volume Required

    5 ml whole blood or 11 ug extracted DNA

    Minimum Required

    3 ml whole blood

    Transport

    Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday within 24 hours of collection.

    Stability

    Whole blood can be refrigerated until shipment.

    Unacceptable conditions

    Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.

    Specimen Handling

    Do not heat, freeze or centrifuge blood before shipment. Refrigerate sample until shipment.

Days Performed

Mon - Fri 9:00am to 4:00pm

Reported

6-8 weeks

CPT

81302, 81404, 81406, 81304

Disease Information

Clinical Features:

MECP2-related disorders include: classic Rett syndrome, atypical Rett syndrome, and very mild learning disabilities in females, and neonatal encephalopathy in males and syndromic or nonsyndromic mental retardation syndromes in males. Mutations in the ARX gene lead to different nonsyndromic as well as syndromic forms of mental retardation: Partington syndrome (PRTS), X-linked infantile spasms syndrome (ISSX), X-linked lissencephaly with abnormal genitalia (XLAG), X-linked myoclonic epilepsy with spasticity and intellectual disability (XMESID), and non syndromic X-linked mental retardation (MRX). More recently, ARX mutations have been identified in several women with isolated agenesis of the corpus callosum (Proud syndrome) and in men with hydranencephaly. The spectrum of phenotypes corresponding to CDKL5-related encephalopathy includes the following: patients with some of the diagnostic criteria of Rett early onset seizure variant, patients characterized by severe encephalopathy with refractory seizures, patients with X-linked infantile spasms and finally, patients with autistic features.

Molecular Genetics:

The MECP2 (Methyl CpG Binding Protein 2) gene is located on Xq28 and contains four exons. MECP2 is a transcriptional repressor protein that is known to possess two critical functional regions, the methyl binding domain (MBD) which binds specifically to DNA at methylated CpG's, and the transcriptional repression domain (TRD) that is responsible for recruiting other proteins that mediate transcription repression. DNA methylation-dependent repression is important for X-chromosome inactivation (XCI) and genomic imprinting. More than 200 pathogenic mutations including missense, nonsense, and deletion mutations have been identified throughout the MECP2 gene. ARX is located on Xp22 and contains 5 coding exons. Mutations identified in ARX have included polyalanine repeat tract expansions, missense mutations, nonsense mutations, premature termination mutations, frameshift mutations, splice site mutations, duplication/insertion mutations, and large deletions. CDKL5 is located on Xp22 and contains 20 coding exons. CDKL5 is involved in mediating the phosphorylation of the methyl-CpG-binding protein 2 (MECP2). More than 30 pathogenic mutations including missense, nonsense, splice-site and small insertion and deletion mutations have been identified throughout the CDKL5 gene. Germline mosaicism and de novo mutations have been reported.

Test Methods:

We offer full gene sequencing and deletion duplication testing of all coding exons and intron/exon boundaries for MECP2, ARX and CDKL5. These tests can be ordered together as a panel or separately. PCR amplification and sequencing is performed on all coding exons including splice junctions. The patient’s gene sequence is then compared to a reference sequence. Sequence variants are classified as mutations, variants of unknown significance or benign variants unrelated to disease. Variants of unknown significance may warrant further studies in the patient and other family members. Large deletions and duplications will be detected using multiplex ligation-dependent probe amplification assay MLPA). Mutations in promoters, deep intronic regions and other regulatory regions will not be identified with this assay.

Detection Rate:

Point mutations have been identified in 70-80% of girls with classic Rett syndrome and 20% of girls with a variant diagnosis. MECP2 deletions are found in approximately 20-30% of girls with classic Rett syndrome and 3% of girls with atypical forms of Rett syndrome. Duplication of the MECP2 gene is detected in 17% of the cases with the specific MECP2 duplication phenotype. Mutations in the ARX gene are detected in 7-10% of cases with XLMR. Mutations in the CDKL5 gene are identified in about 10-17% of the girls affected with early onset seizures or a Rett like phenotype.

Related Tests:

Rett syndrome: MECP2 Sequencing & Deletion/Duplication Analysis Atypical Rett syndrome: CDKL5 Gene Sequencing & Deletion/Duplication Analysis Infantile Spasms: ARX Sequencing & Deletion/Duplication Analysis Congenital Variant of Rett syndrome: FOXG1 Sequencing & Deletion/Duplication Analysis Known mutation analysis is available to family members for mutations previously identified by sequence analysis or deletion/duplication analysis. Prenatal testing is available to adult females who are confirmed carriers of mutations. Please contact the laboratory director to discuss appropriate testing prior to collecting a prenatal specimen.

Results:

Test results with interpretation will be mailed and/or faxed to the referring physician or laboratory following completion of the test. Additional reports will be provided as requested.

Utility:

The clinical utility of such testing is to support a clinical diagnosis of the disease, facilitate genetic counseling, assess the risk to other first degree relatives and to facilitate testing of at - risk family members.

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215-590-5221