Congenital Variant Rett Syndrome: FOXG1 Gene Sequencing

Condition Description

Mutations and deletions of the FOXG1 gene (14q13) cause a developmental disorder known as a Congenital Variant of Rett syndrome.  Common features include severe postnatal microcephaly, severe intellectual disability with absent language, apraxia, hypogenesis of the corpus callosum, jerky movements and generalized seizures.  These individuals have normal body measurements at birth but then have slow growth after leading to low weight and low normal stature.  Sleep was reported to be disrupted starting in infancy and stereotypical hand movements were observed.  Unlike Rett syndrome, individuals with a FOXG1 mutation do NOT have any periods of normal development.  

Duplications of the FOXG1 gene have been associated with developmental epilepsy, intellectual disability, and severe speech impairment. 

For patients with suspected Congenital Variant of Rett syndrome, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

References:
  • Kortum et al. (2011). J Med Genet, 48:396-406.
  • OMIM #613454: Congenital Variant Rett syndrome
  • OMIM #164874: FOXG1 gene

Genes (1)

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Indications

This test is indicated for:
  • Confirmation of a clinical diagnosis of Congenital Variant Rett syndrome.
  • Carrier testing in adults with a family history of Congenital Variant Rett syndrome.

Methodology

PCR amplification of 1 exon contained in the FOXG1 gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.

Detection

Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's clinical and/or biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (eglgc@egl-eurofins.com).
Submit only 1 of the following specimen types
Saliva
SLV

Requirements
Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.
Whole Blood (EDTA)
WBP

Requirements
EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.
DNA, Isolated
DNA

Requirements
Microtainer
8µg
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.
  • Deletion/duplication analysis of the FOXG1 gene by CGH array is available for those individuals in whom sequence analysis is negative.
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available only for known familial mutations to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

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