Walker-Warburg Syndrome: POMT2 Gene Deletion/Duplication
Condition Description
Walker-Warburg syndrome (WWS) is the most severe of the dystroglycanopathies. Features are similar to muscle-eye-brain disease, but there is phenotypic heterogeneity. Affected individuals lack spontaneous movement at birth, have a weak cry and suck, and have generalized hypotonia and weakness. Feeding difficulties can require gastronomy feeding. They may have microcephaly, hydrocephalus, contractures, cleft lip and palate, seizures, genital anomalies in males, and encephalocele. Eye abnormalities can include congenital cataracts, microphthalmia, glaucoma, and iris malformations. Brain malformations can include complete lissencephaly type II with pontocerebellar hypoplasia with Dandy-Walker malformation, fusion of the hemispheres, and absence of corpus callosum. Life expectancy is often a few years.
Serum creatine kinase (CK) levels are elevated at 2-15 times normal. Histology reveals a general myopathic pattern, and immunohistochemistry shows deficiency of glycosylated alpha dystroglycan while laminin alpha 2 (merosin) levels can be normal or reduced.
WWS is an autosomal recessive disorder with genetic heterogeneity. Approximately 20% of individuals with a clinical diagnosis of WWS have mutations in the POMT1 gene (9q34.1). Mutations have also been found in the POMT2, FKTN, FKRP, POMGNT1, and LARGE genes. Other as yet unidentified genes are thought to be a major cause of WWS.
For patients with suspected WWS, 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
- Bonnemann, Carsten. Personal communication. July 8, 2009.
- Conti Reed, U. Congenital muscular dystrophy part I: A review of phenotypical and diagnostic aspects. Arq Neuropsiquiatr. 2009; 67:144-168.
- GeneTests: Congenital Muscular Dystrophy Overview. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene∂=cmd-overview
- Mendell, JR et al. The congenital muscular dystrophies: Recent advances and molecular insights. Ped and Dev Pathology. 2006; 9:427-443.
Genes (1)
Indications
This test is indicated for:
- Confirmation of a clinical diagnosis of Walker-Warburg syndrome in an individual in whom sequence analysis was negative
- Carrier testing in adults with a family history of Walker-Warburg syndrome in whom sequence analysis was negative
Methodology
DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.
Detection
Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations.
Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.
Specimen Requirements
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
3µg
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Special Instructions
Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.
Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.
Related Tests
- Sequence analysis of the POMT2 gene is required before deletion/duplication analysis
- Analysis of the POMT1, FKTN, FKRP, POMGNT1, and LARGE genes is also available.
- Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.