Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach

Abstract

Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1—GDAP1, SH3 domain and tetratricopeptide repeats-containing protein 2—SH3TC2, histidine-triad nucleotide binding protein 1—HINT1) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22 % of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3 % patients. Apart from a newly described founder mutation in GDAP1, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the SH3TC2 gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies.

Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing

“…21,26,27 Here we evaluated the performance of different SNP extraction strategies and PLINK parameters for homozygosity mapping, using WES data of patients with AR HSP and AR CMT. We determined the parameters for detection of ROHs from WES data with high sensitivity (84.4%) and specificity (82.4%), using high-density SNP arrays as a reference, and implemented them in the publicly available HOMWES tool.…”

“…Homozygosity mapping based on SNP array data was performed as described previously. 21 To measure the accuracy of ROH detection from WES data, we used the SNP array data as a reference and estimated the specificity and sensitivity of detection as follows: We defined false-positive ROH as present in WES-derived data, but not in the SNP array-derived data, and false-negative ROHs were the ones found in SNP array-derived and not in WES-derived data. The Z-test 22 was used to assess the differences between the mean sensitivity/specificity estimated in the training set versus the test set of individuals.…”

Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy

“…18 Here, we provide genetic and functional evidence that SGPL1 is a candidate AR-CMT gene. The associated phenotype is distinct from other AR-CMT2 subtypes and is characterized by acute/subacute onset, unilateral motor deficit in one patient, and episodes of mononeuropathy with a tendency for improvement in both patients.…”

Clinical and genetic characteristics of autosomal recessive axonal neuropathy with neuromyotonia in Russian patients

“…Описаны более 60 семей с АР-аксональной нейропатией и нейромио-тонией (АР-АНМ), обусловленными мутациями в гене HINT1. Показано, что мутации в этом гене обнаружива-ются у 80 % всех больных с обсуждаемой ком би нацией симптомов [6]. Большинство семей с АР-АНМ выяв-лено в странах Восточной Европы и Турции [7,8].…”