Manisha Karamala Yalapalli, Fasaludeen Alfiya, Poulose Prashanth, Menon Ramshekhar, Thomas Bejoy, Nair Sruthi S, Cherian Ajith, Divya Kalikavil Puthanveedu, Sundaram Soumya
From the Department of Neurology (K.Y.M., A.F., P.P., S.S.N., A.C., K.P.D.); Pediatric Neurology and Neurodevelopmental Disorders (R.M., S.S.); and Department of Imaging Sciences and Intervention Radiology (B.T.), Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Thiruvananthapuram, Kerala, India.
Neurol Genet. 2024 Aug 22;10(5):e200190. doi: 10.1212/NXG.0000000000200190. eCollection 2024 Oct.
Next-generation sequencing (NGS) has expedited the diagnostic process and unearthed many rare disorders in leukodystrophy (LD) and genetic leukoencephalopathy (gLE). Despite the progress in genomics, there is a paucity of data on the distribution of genetic white matter disorders (WMDs) and the diagnostic utility of NGS-based assays in a clinical setting. This study was initiated to explore the clinical, radiologic, and genetic spectrum of LD and gLE in the Indian population and also to estimate the diagnostic yield of clinical exome sequencing (CES).
This is a retrospective descriptive analysis of patients with a diagnosis of genetic WMDs from a single tertiary referral center who had CES performed as part of the diagnostic evaluation between January 2016 and December 2021. The demographic, clinical, radiologic, and genetic data were collected. The variants were classified using the American College of Medical Genetics and Genomics criteria. Pathogenic and likely pathogenic variants were included in the calculation of the diagnostic yield.
In the study period, 138 patients were clinically diagnosed with either LD or gLE, of which 86 patients underwent CES. Pathogenic variants, likely pathogenic variants, and variants of uncertain significance with phenotype match were seen in 40 (41.8%), 13 (29.1%), and 15 (15.2%) patients, respectively. The mean age at onset in these 68 patients was 6.35 years (range 1 month-39 years), and 38 (55.9%) were male. LDs and gLE were diagnosed in 31 and 37 patients, respectively. 56 patients (71.8%) had autosomal recessive inheritance. The common clinical presentations were developmental delay (23.5%), psychomotor regression (20.6%), progressive myoclonic epilepsy syndrome (19.1%), and spastic ataxia (14.7%). Myelin disorders (48.5%) and leuko-axonopathies (41.2%) were the commonest type of disorders. The most frequently identified genes were , , , , , , and . The diagnostic yield of the study was 61.6% (53/86), which increased to 79.1% when VUS with phenotype match were included.
This study demonstrated a high diagnostic yield from proband-only CES in the evaluation of genetic WMDs and should be considered as a first-line investigation for genetic diagnosis.
This study provides Class IV evidence that proband-only clinical exome sequencing is a useful "first-line investigation" for patients with genetic white matter disorders.
下一代测序（NGS）加快了诊断进程，并发现了许多脑白质营养不良（LD）和遗传性脑白质病（gLE）中的罕见疾病。尽管基因组学取得了进展，但关于遗传性白质疾病（WMDs）的分布以及基于NGS的检测方法在临床环境中的诊断效用的数据仍然匮乏。本研究旨在探索印度人群中LD和gLE的临床、放射学和遗传学谱，并评估临床外显子组测序（CES）的诊断率。
这是一项对来自单一三级转诊中心的诊断为遗传性WMDs患者的回顾性描述性分析，这些患者在2016年1月至2021年12月期间接受了CES作为诊断评估的一部分。收集了人口统计学、临床、放射学和遗传学数据。使用美国医学遗传学与基因组学学会标准对变异进行分类。致病性和可能致病性变异被纳入诊断率的计算。
在研究期间，138例患者临床诊断为LD或gLE，其中86例患者接受了CES。分别在40例（41.8%）、13例（29.1%）和15例（15.2%）患者中发现了致病性变异、可能致病性变异以及与表型匹配的意义未明变异。这68例患者的平均发病年龄为6.35岁（范围1个月 - 39岁），38例（55.9%）为男性。分别在31例和37例患者中诊断出LD和gLE。56例患者（71.8%）具有常染色体隐性遗传。常见的临床表现为发育迟缓（23.5%）、精神运动倒退（20.6%）、进行性肌阵挛癫痫综合征（19.1%）和痉挛性共济失调（14.7%）。髓鞘疾病（48.5%）和白质 - 轴索性疾病（41.2%）是最常见的疾病类型。最常鉴定出的基因是 ， ， ， ， ， ， 和 。该研究的诊断率为61.6%（53/86），当纳入与表型匹配的意义未明变异时，诊断率提高到79.1%。
本研究表明，仅对先证者进行CES在遗传性WMDs评估中具有较高的诊断率，应被视为基因诊断的一线检查。
本研究提供了IV类证据，即仅对先证者进行临床外显子组测序是遗传性白质疾病患者有用的“一线检查”。
