Expanding the Phenotype Associated With the NEFL Mutation Neuromuscular Disease in a Family With Overlapping Myopathic and Neurogenic Findings
Expanding the Phenotype Associated With the NEFL Mutation Neuromuscular Disease in a Family With Overlapping Myopathic and Neurogenic Findings
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DOI：
10.1001/jamaneurol.2014.1432
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发表时间：
2014-11-01
期刊：
影响因子：
29
通讯作者：
Beggs, Alan H.
中科院分区：
文献类型：
--
作者：
Agrawal, Pankaj B.;Joshi, Mugdha;Beggs, Alan H.
重要的是，较新的测序技术与传统的基因图谱技术相结合，如连锁分析，可以帮助确定病因不明的罕见疾病患者的疾病遗传基础。目的阐明一家系中一位母亲和她的三个儿子的神经肌肉疾病的分子病因。设计、设置和参与者4名受影响的成员中有2名表现为线状肌病，这是先天性肌病的一种常见亚型，而另外2名成员患有非特异性肌病。对4个家系成员的DNA样本进行单核苷酸多态连锁分析，并对先证者进行全基因组测序。对肌肉活检标本进行实时定量逆转录聚合酶链式反应、免疫荧光和Western印迹分析。主要结果和指标全基因组测序和连锁分析发现了一个解释该表型的基因变异。结果我们在所有受影响的成员中发现了一个新的神经丝轻多肽(NEFL)无义突变。NEFL突变以前曾被认为与人类的Charcot-Marie-Tooth病有关。这导致我们重新评估诊断，我们认识到一些发现，特别是与肌肉活检标本和肌电图相关的结果，与神经源性疾病一致。结论已知NEFL突变可导致人类的Charcot-Marie-Tooth病和小鼠的运动神经元病。我们报告在一个临床表现为先天性肌病的家系中发现一个NEFL突变。我们也描述了在这个家族中，肌病和神经源性发现之间的潜在重叠。这些发现扩大了与NEFL突变相关的疾病的表型谱。这项研究是基因组方法识别导致异质性神经肌肉疾病的意外基因中潜在致病突变的能力的一个例子。
IMPORTANCE Newer sequencing technologies in combination with traditional gene mapping techniques, such as linkage analysis, can help identify the genetic basis of disease for patients with rare disorders of uncertain etiology. This approach may expand the phenotypic spectrum of disease associated with those genetic mutations.OBJECTIVE To elucidate the molecular cause of a neuromuscular disease among a family in which 4 members, a mother and her 3 sons, were affected.DESIGN, SETTING, AND PARTICIPANTS Two of 4 affected members manifested nemaline myopathy, a common subtype of congenitalmyopathy, while the other 2 had a nonspecific myopathy. Single-nucleotide polymorphism-based linkage analysis was performed on DNA samples from the 4 affected family members, and whole-genome sequencing was performed in the proband. Real-time quantitative reverse transcription-polymerase chain reaction, immunofluorescence, and Western blot analysis were performed on muscle biopsy specimens.MAIN OUTCOMES AND MEASURES Whole-genome sequencing and linkage analysis identified a variant in a gene that explains the phenotype.RESULTS We identified a novel neurofilament light polypeptide (NEFL) nonsense mutation in all affected members. NEFL mutations have been previously linked to Charcot-Marie-Tooth disease in humans. This led us to reevaluate the diagnosis, and we recognized that several of the findings, especially those related to the muscle biopsy specimens and electromyography, were consistent with a neurogenic disease.CONCLUSIONS AND RELEVANCE NEFL mutations are known to cause Charcot-Marie-Tooth disease in humans and motor neuron disease in mice. We report the identification of an NEFL mutation in a family clinically manifesting congenitalmyopathy. We also describe potential overlap between myopathic and neurogenic findings in this family. These findings expand the phenotypic spectrum of diseases associated with NEFL mutations. This study is an example of the power of genomic approaches to identify potentially pathogenic mutations in unsuspected genes responsible for heterogeneous neuromuscular diseases.