第八届北京罕见病学术大会暨2020京津冀罕见病学术大会征文（4)

北京大学第一医院

Huifang Yan*1，2，3， Haoran Ji*1，4， Thomas Kubisiak2， Ye Wu1， Jiangxi Xiao5， Qiang Gu1， Yanling Yang1， Han Xie1， Taoyun Ji1， Kai Gao1， Dongxiao Li1，6， Zhen Shi1， Ruoyu Duan1， Yuwu Jiang1，3，7， Margit Burmeister^，2，8， Jingmin Wang^，1，3，7

摘要

Objective Hypomyelinating leukodystrophy (HLD) is a group of disorders characterized by myelin deficit based on MRI of the developing brain. Early clinical presentations initiating pediatric attention often include delays in motor ability， intellectual disability， cerebellar signs， and ataxia. Due to clinical and genetic heterogeneity， ~25% of all HLDs cases remain unresolved in our HLD cohort. This study aims to identify genetic causes and novel disease-causing genes in patients with unexplained hypomyelinating leukodystrophy.

Methods Out of 205 cases in our HLDs cohort， genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes diagnostically solved 155 cases (~75%). Here， trio-based exome sequencing was performed on 20 index patients and their parents selected from the remaining 50 unresolved cases. Through comprehensive analysis， in which we not only look through those genes that known related to HLDs， but also track the promising candidate genes.

Results In 13 of 20 trios， potentially causative variants were detected in four previously known genes TUBB4A， POLR1C， POLR3A， SOX10 and five candidate genes TMEM106B， TMEM63A， DEGS1， PTPRA and REM2， of which， three were confirmed to be novel disease-causing genes of HLDs to date. Of all 17 variants in nine genes， 12 were novel and nine presented de novo.

Conclusion Our analysis further increases the diagnostic yield of unexplained hypomyelinating leukodystrophies. Paying attention to promising variants and dynamically tracking candidate genes help us identify novel genes and clarify the genetic diagnosis in time. De novo dominant variants as a cause of HLDs are with a high frequency of 9/13 in our cohort， which suggest that trio-based WES is an advanced strategy for unexplained HLDs.