Diagnosis; Mutation Confirmation

An estimated 80% of individuals with clinically confirmed HNPP will harbour a deletion of the PMP22 gene region. A further 20% will harbour point mutations in the PMP22 coding sequence. 70%-80% of individuals with CMT1A will harbour a duplication of the PMP22 gene region

Establish or confirm diagnosis

CMT1A is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. It is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually become symptomatic between age five and 25 years.

All coding exons and 20 bp of flanking intronic sequence are enriched using an LHSC custom targeted hybridization protocol (Roche Nimblegen), followed by high throughput sequencing (Illumina). Sequence variants and copy number changes are assessed and interpreted using clinically validated algorithms and commercial software (SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; … All coding exons and 20 bp of flanking intronic sequence are enriched using an LHSC custom targeted hybridization protocol (Roche Nimblegen), followed by high throughput sequencing (Illumina). Sequence variants and copy number changes are assessed and interpreted using clinically validated algorithms and commercial software (SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; and Alamut Visual). All exons have >1000x mean read depth coverage, with a minimum 200x coverage at a single nucleotide resolution. This assay meets the sensitivity and specificity of combined Sanger sequencing and MLPA copy number analysis. All variants interpreted as either ACMG category 1, 2, or 3 (pathogenic, likely pathogenic, VUS; PMID: 25741868) are confirmed using Sanger sequencing, MLPA, or other assays. ACMG category 4 and 5 variants (likely benign, benign) are not reported, but are available upon request. View more

All variants interpreted as either ACMG category 1, 2, or 3 (pathogenic, likely pathogenic, VUS; PMID: 25741868) are confirmed using Sanger sequencing, MLPA, or other assays. ACMG category 4 and 5 variants (likely benign, benign) are not reported, but are available upon request.

Tests performed
Entire test performed in-house

Test performance comments
Testing provided in a state of the art purpose built Molecular Diagnostics facility.

The diagnosis of HNPP is established in an adult with recurrent focal compression neuropathies who has a family history consistent with autosomal dominant inheritance. PMP22 is the only gene known to be associated with HNPP. A contiguous gene deletion of chromosome 17p11.2 that includes PMP22 is present in approximately 80% … The diagnosis of HNPP is established in an adult with recurrent focal compression neuropathies who has a family history consistent with autosomal dominant inheritance. PMP22 is the only gene known to be associated with HNPP. A contiguous gene deletion of chromosome 17p11.2 that includes PMP22 is present in approximately 80% of affected individuals; the remaining 20% have a mutation in PMP22. Testing is available in clinical laboratories. View more

Is proficiency testing performed for this test? Help
No

Software used to interpret novel variations Help
SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; and Alamut Visual

Laboratory's policy on reporting novel variations Help
All variants interpreted as either ACMG category 1, 2, or 3 (pathogenic, likely pathogenic, VUS; PMID: 25741868) are confirmed using Sanger sequencing, MLPA, or other assays. ACMG category 4 and 5 variants (likely benign, benign) are not reported, but are available upon request.