Charcot-Marie-Tooth disease (CMT) is a syndrome of a hereditary neurodegenerative condition affecting the peripheral nervous system and is a single gene disorder. Deep phenotyping coupled with advanced genetic techniques is critical in discovering new genetic defects of rare genetic disorders such as CMT.

We applied multidisciplinary investigations to examine the neurophysiology and nerve pathology in a family that fulfilled the diagnosis of CMT2. When phenotype-guided first-tier genetic tests and whole-exome sequencing did not yield a molecular diagnosis, we conducted full genome analysis by examining phased whole-genome sequencing and whole-genome optical mapping data to search for the causal variation. We then performed a systematic review to compare the reported patients with interstitial microdeletion in the short arm of chromosome 4.

In this family with CMT2, we reported the discovery of a heterozygous 85-kb microdeletion in the short arm of chromosome 4 (4p16.3)[NC_000004.12:g.1733926_1819031del] spanning 3 genes [TACC3 (intron 6-exon 16), FGFR3 (total deletion), and LETM1 (intron 10-exon14)] that cosegregated with disease phenotypes in family members. The clinical features of peripheral nerve degeneration in our family are distinct from the well-known 4p microdeletion syndrome of Wolf-Hirschhorn syndrome, in which brain involvement is the major phenotype.

In summary, we used the full genome analysis approach to discover a new microdeletion in a family with CMT2. The deleted segment contains 3 genes (TACC3, FGFR3, and LETM1) that likely play a role in the pathogenesis of nerve degeneration.

腓骨肌萎缩症 (CMT) 是一种影响周围神经系统的遗传性神经退行性疾病综合征，是一种单基因疾病。深度表型分析与先进的遗传技术相结合对于发现 CMT 等罕见遗传疾病的新遗传缺陷至关重要。

我们应用多学科调查来检查一个符合 CMT2 诊断的家庭的神经生理学和神经病理学。当表型引导的一级基因检测和全外显子组测序无法产生分子诊断时，我们通过检查分阶段全基因组测序和全基因组光学图谱数据进行全基因组分析，以寻找因果变异。然后，我们进行了系统回顾，以比较所报告的 4 号染色体短臂间质性微缺失患者。

在这个 CMT2 家族中，我们报告了在 4 号染色体短臂 (4p16.3)[NC_000004.12:g.1733926_1819031del] 中发现的杂合 85-kb 微缺失，跨越 3 个基因 [TACC3（内含子 6-外显子16） 、FGFR3（完全缺失）和LETM1（内含子 10-外显子 14）] 与家族成员的疾病表型共分离。我们家周围神经变性的临床特征与众所周知的 Wolf-Hirschhorn 综合征的 4p 微缺失综合征不同，后者以脑部受累为主要表型。

总之，我们使用全基因组分析方法在 CMT2 家族中发现了新的微缺失。删除的片段包含 3 个基因（TACC3、FGFR3和LETM1），它们可能在神经变性的发病机制中发挥作用。