Genetic Survey of Autosomal Recessive Peripheral Neuropathy Cases Unravels High Genetic Heterogeneity in a Turkish Cohort

Abstract

Background and ObjectivesInherited peripheral neuropathies (IPNs) are a group of genetic disorders of the peripheral nervous system in which neuropathy is the only or the most predominant clinical feature. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease. Autosomal recessive CMT (ARCMT) is generally more severe than dominant CMT and its genetic basis is poorly understood due to high clinical and genetic diversity. Here, we report clinical and genetic findings from 56 consanguineous Turkish families initially diagnosed with CMT disease.MethodsWe initially screened the GDAP1 gene in our cohort as it is the most commonly mutated ARCMT gene. Next, whole-exome sequencing and homozygosity mapping based on whole-exome sequencing (HOMWES) analysis was performed. To understand the molecular impact of candidate causative genes, functional analyses were performed in patient primary fibroblasts.ResultsBiallelic recurrent mutations in the GDAP1 gene have been identified in 6 patients. Whole-exome sequencing and HOMWES analysis revealed 16 recurrent and 13 novel disease-causing alleles in known IPN-related genes and 2 novel candidate genes: 1 for a CMT-like disease and 1 for autosomal recessive cerebellar ataxia with axonal neuropathy. We have achieved a potential genetic diagnosis rate of 62.5% (35/56 families) in our cohort. Considering only the variants that meet the American College for Medical Genetics and Genomics (ACMG) classification as pathogenic or likely pathogenic, the definitive diagnosis rate was 55.35% (31/56 families).DiscussionThis study paints a genetic landscape of the Turkish ARCMT population and reports additional candidate genes that might help enlighten the mechanism of pathogenesis of the disease.

Clinical and Genetic Survey for Charcot-Marie-Tooth Neuropathy Based on the Findings in Turkey, a Country with a High Rate of Consanguineous Marriages

“…Initial filtering of the WES data with relaxed filtering criteria (MAF < 0.05) for known neurology disease genes has a major contribution to the success rate since it identifies the mutations in the genes that overlap with other neurological diseases like hereditary spastic paraplegia and amyotrophic lateral sclerosis. 66 …”

Genetic Survey of Autosomal Recessive Peripheral Neuropathy Cases Unravels High Genetic Heterogeneity in a Turkish Cohort

“…In the Article "Genetic Survey of Autosomal Recessive Peripheral Neuropathy Cases Unravels High Genetic Heterogeneity in a Turkish Cohort" by Candayan et al 1 , the affiliations for the fourth and fifth authors listed in the Location column of the Appendix should be as follows. The affiliation for Ays ¸e Nur Özdag Acarlı: "Neuromuscular Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey."…”

“…In the Article “Genetic Survey of Autosomal Recessive Peripheral Neuropathy Cases Unravels High Genetic Heterogeneity in a Turkish Cohort” by Candayan et al 1 , the affiliations for the fourth and fifth authors listed in the Location column of the Appendix should be as follows. The affiliation for Ayşe Nur Özdağ Acarlı: “Neuromuscular Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey.” The affiliations for Derek Atkinson: “Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Belgium; Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.” The publisher regrets the errors.…”