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Online mutation report
Diagnosis of gene dosage alterations at the PMP22 gene using MAPH
  1. S M Akrami1,3,
  2. J S Rowland2,
  3. G R Taylor2,
  4. J A L Armour1
  1. 1Institute of Genetics, University of Nottingham, Nottingham, UK
  2. 2Regional DNA Laboratory, Ashley Wing, St James’s University Hospital, Leeds, UK
  3. 3EMRC, Tehran University of Medical Sciences, Iran
  1. Correspondence to:
 Dr J A L Armour
 Institute of Genetics, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK; john.armournottingham.ac.uk

https://doi.org/10.1136/jmg.40.11.e123

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    Genomic rearrangements due to submicroscopic duplications or deletions are responsible for many inherited disorders, and a gene (or genes) sensitive to dosage alterations may be involved in these structural rearrangements. The segment involved is generally smaller than 2 Mb and cannot be detected by conventional karyotyping.1 Charcot-Marie-Tooth disease type 1A (CMT1A) [OMIM #118220] and hereditary neuropathy with liability to pressure palsies (HNPP) [OMIM #162500] are well characterised as genomic disorders.2 By a gene dosage mechanism, CMT1A or HNPP respectively result from duplication or deletion of a 1.4 Mb DNA fragment in 17p12 containing the PMP22 gene. Amplification of the PMP22 gene from two copies in normal people to three and even (in severe cases) four copies has been detected in CMT1A cases, and deletion of the gene to one copy results in HNPP. CMT1A/HNPP are caused by a reciprocal unequal crossover event arising from the misalignment of homologous repeat sequences, CMT1A-REPs, which flank the 1.4 Mb region. These 24 kb duplicons are 98.7% identical and are thought to mediate this misalignment.1,3 In a minority of cases, point mutations in the same gene can also result in CMT1A or HNPP.

    These two distinct conditions are autosomal dominant traits in a clinically and genetically heterogeneous group of peripheral neuropathies termed hereditary motor and sensory neuropathies (HMSN). The overall estimated prevalence of HMSN is about 1 in 2500,4 and CMT1A is the most common inherited peripheral neuropathy, with a prevalence of 10–40/100 000.5 A European collaborative study reported the duplication in 70.7% of unrelated CMT1A patients and the deletion of the same region in 84% of HNPP cases.6

    There is a wide range of approaches for molecular diagnosis of CMT1A and HNPP. These approaches can be classified as (a) methods detecting rearrangements and (b) quantitative methods. …

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