Search for Additional Pathogenic Variants to Explain Variation in PMP22 -Related Neuropathies

Neurology Genetics, vol. 11, pp. e200315

Abstract

Background and Objectives: The aim of this study was to investigate whether the considerable phenotypic variation in Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) is due to additional pathogenic coding variants in severely affected patients, by screening a panel of neuropathy-related genes. Methods: In this cross-sectional study, the extremes of the spectrum of 742 patients with genetically confirmed CMT1A and HNPP were selected, based on disability as assessed using the Overall Neuropathy Limitation Scale (ONLS). The ONLS data of 183 patients with CMT1A and 102 with HNPP showed a Gaussian distribution. A next-generation sequencing panel containing 177 neuropathy-related genes was tested in a selected group of 20 patients with mild CMT1A, 24 with severe CMT1A, 25 with mild HNPP, and 25 with severe HNPP. Results: gene was identified in a severe CMT1A case. Heterozygous pathogenic variants in autosomal recessive neuropathy-related genes were found in 2 patients with severe CMT1A and in 2 with mild HNPP. Discussion: copy-number alterations, further genetic screening for pathogenic variants in CMT-related genes is warranted only in severe cases.

Authors 9

1. Barbara W. van Paassen

   Erasmus MC

   Affiliation as printed

   Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands;

2. Camiel Verhamme

   Amsterdam University Medical Centers

   Affiliation as printed

   Department of Neurology, Amsterdam University Medical Center, the Netherlands;

3. Fred van Ruissen

   Amsterdam University Medical Centers

   Affiliation as printed

   Department of Human Genetics, Amsterdam University Medical Center, the Netherlands;

4. Martin A. Haagmans

   Amsterdam University Medical Centers

   Affiliation as printed

   Department of Human Genetics, Amsterdam University Medical Center, the Netherlands;

5. Marcel G. W. Dijkgraaf

   Amsterdam University Medical Centers

   Affiliation as printed

   Department of Epidemiology and Data Science, Amsterdam University Medical Center, the Netherlands;

6. Marianne de Visser

   Amsterdam University Medical Centers

   Affiliation as printed

   Department of Neurology, Amsterdam University Medical Center, the Netherlands;

7. Frank F. Baas Aachen Department of Clinical Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Genetics, Leiden University Medical Center, the Netherlands

8. Anneke J. van der Kooi corresponding

   Amsterdam University Medical Centers

   Affiliation as printed

   Department of Neurology, Amsterdam University Medical Center, the Netherlands;

9. Marian A. J. Weterman corresponding Aachen Department of Clinical Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Genetics, Leiden University Medical Center, the Netherlands