Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐ related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.

中文翻译：

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估计脑白质营养不良的相对频率以及下一代测序时代携带者筛查的建议。


脑白质营养不良是一组异质性遗传性疾病，其特征是磁共振成像 (MRI) 上的脑白质信号异常以及主要累及髓磷脂的细胞成分。之前的估计表明，脑白质营养不良的总体发病率为七千分之一，但尚未描述相对于其他疾病的特定诊断的频率。下一代测序方法提供了重新定义我们对不同脑白质营养不良相对频率的理解的机会。我们评估了 49,000 多个外显子组中所有 30 种脑白质营养不良（与 55 个基因相关）的相对频率。我们发现了一些以前被认为非常罕见的疾病，包括 Aicardi Goutières 综合征、 TUBB4A相关脑白质营养不良、过氧化物酶体生物发生障碍、POLR3 相关脑白质营养不良、白质消失和 Pelizaeus-Merzbacher 病。尽管这些病症的相对频率较高，但携带者筛查实验室定期仅测试 55 个脑白质营养不良相关基因中的 20 个，并且根本不测试或仅测试某些高频疾病的一个或几个基因。以前认为非常罕见的脑白质营养不良的相对频率表明这些疾病可能受益于扩大的携带者筛查。