Inherited 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.

We 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.

Biallelic 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).

This 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.

遗传性周围神经病变 (IPN) 是一组周围神经系统的遗传性疾病，其中神经病变是唯一或最主要的临床特征。最常见的 IPN 类型是 Charcot-Marie-Tooth (CMT) 病。常染色体隐性遗传 CMT (ARCMT) 通常比显性 CMT 更严重，并且由于临床和遗传多样性高，对其遗传基础知之甚少。在这里，我们报告了最初被诊断患有 CMT 疾病的 56 个近亲土耳其家庭的临床和遗传学发现。

我们最初在我们的队列中筛选了GDAP1基因，因为它是最常见的突变 ARCMT 基因。接下来，进行了基于全外显子组测序（HOMWES）分析的全外显子组测序和纯合子图谱。为了了解候选致病基因的分子影响，对患者原代成纤维细胞进行了功能分析。

已在 6 名患者中发现GDAP1基因的双等位基因复发突变。全外显子组测序和 HOMWES 分析揭示了已知 IPN 相关基因中的 16 个复发等位基因和 13 个新的致病等位基因和 2 个新的候选基因：1 个用于 CMT 样疾病，1 个用于常染色体隐性遗传性小脑性共济失调伴轴突神经病变。在我们的队列中，我们已经实现了 62.5%（35/56 个家庭）的潜在基因诊断率。仅考虑符合美国医学遗传学和基因组学 (ACMG) 分类为致病或可能致病的变异，最终诊断率为 55.35%（31/56 个家庭）。

这项研究描绘了土耳其 ARCMT 人群的遗传景观，并报告了可能有助于阐明该疾病发病机制的其他候选基因。