Studies Of Hereditary Neurological Disease: Disease Gene Identification

这项研究计划的目的是调查遗传性神经疾病的原因，目的是为这些疾病开发有效的治疗方法。遗传外展计划允许识别和描述患有遗传性神经疾病的患者和家庭的特征。过去一年的具体研究成就包括马里在基因研究方面的合作，以及对报告外显子组测序二次基因组发现的程序的审查。 通过马里合作，对120多个家庭进行了评估，在24个家庭中进行了17种不同的基因诊断。我们目前的重点是剩下的具有感兴趣的表型、常染色体隐性遗传和血缘关系的家庭。外显子组测序和分离分析通过NISC进行候选基因的鉴定。 我们评估了一个马里家庭，其中三个人患有遗传性痉挛截瘫(HSP)和远端肌肉萎缩和感觉丧失。HSP小组检测发现了KIF5A(c.1086G&gt；C，p.Lys362Asn)的一个新的杂合性错义突变，该突变与疾病(SPG10)分离。Lys362在物种间高度保守，Lys362Asn被预测具有破坏性。这项研究表明，撒哈拉以南非洲地区存在热休克蛋白，尽管可能被低估了。DNA测序效率的提高和成本的降低将使在发展中国家诊断热休克变得更加可行。

The purpose of this research program is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. A genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. Specific research accomplishments in the past year include collaboration in genetic studies in Mali and in a review of procedures for reporting of secondary genomic findings from exome sequencing. Through the Mali collaboration, over 120 families have been evaluated, with more than 17 different genetic diagnoses in 24 families. Our current focus is on the remaining families with phenotypes of interest, autosomal recessive inheritance & consanguinity. Exome sequencing and segregation analysis are done through NISC for candidate gene identification. We evaluated a Malian family in which three individuals had hereditary spastic paraplegia (HSP) and distal muscle atrophy and sensory loss. HSP panel testing identified a novel heterozygous missense mutation in KIF5A (c.1086G>C, p.Lys362Asn) that segregated with the disease (SPG10). Lys362 is highly conserved across species and Lys362Asn is predicted to be damaging. This study shows that HSPs are present in sub-Saharan Africa, although likely underdiagnosed. Increasing efficiency and decreasing costs of DNA sequencing will make it more feasible to diagnose HSPs in developing countries.