Department of Pediatrics, Peking University First Hospital, Beijing, China.
Department of Pediatric Neurology, Capital Institute of Pediatrics, Beijing, China.
J Med Genet. 2019 Feb;56(2):81-88. doi: 10.1136/jmedgenet-2017-105235. Epub 2018 Oct 4.
Mutations in the gene have mainly been reported in female patients with epilepsy. To date, mutations have been reported in hundreds of females and only in 10 mosaic male epileptic patients with mosaicism.
We aimed to investigate the occurrence of mosaic mutations in 42 families comprising at least one patient with -related epilepsy.
Two male patients with mosaic variants were identified using targeted next-generation sequencing. Forty female patients with variants were identified by Sanger sequencing and Multiple Ligation Probe Amplification (MLPA). Microdroplet digital PCR was used to quantify the mutant allelic fractions (MAFs) in 20 families with variants.
Five mosaic individuals, four males and one female, were identified in total. Mosaic variant was confirmed in multiple somatic tissues from one male patient and in blood from the other male patient. Among 22 female patients harbouring a newly occurred variant identified by Sanger sequencing and MLPA, Sanger sequencing revealed two mosaic fathers (9%, 2/22), one with two affected daughters and the other with an affected child. Two asymptomatic mosaic fathers were confirmed as gonosomal mosaicism, with MAFs ranging from 4.16% to 37.38% and from 1.27% to 19.13%, respectively. In 11 families with apparent de novo variants, 1 female patient was identified as a mosaic with a blood MAF of 26.72%.
Our study provides new insights into phenotype-genotype correlations in related epilepsy and the finding of high-frequency mosaicism has important implications for genetic counselling.
基因中的突变主要在患有癫痫的女性患者中报道。迄今为止，已有数百名女性患者发生突变，仅有 10 名镶嵌型男性癫痫患者发生镶嵌突变。
我们旨在调查至少有一名 -相关癫痫患者的 42 个家族中镶嵌突变的发生情况。
使用靶向下一代测序鉴定了两名携带镶嵌 变体的男性患者。通过 Sanger 测序和多重连接探针扩增（MLPA）鉴定了 40 名携带 变体的女性患者。使用微滴式数字 PCR 对携带 变体的 20 个家族的突变等位基因分数（MAF）进行定量。
共鉴定出 5 名镶嵌个体，其中 4 名为男性，1 名为女性。在一名男性患者的多个体组织和另一名男性患者的血液中证实存在镶嵌变体。在 22 名通过 Sanger 测序和 MLPA 鉴定为新发生 变体的女性患者中，Sanger 测序显示 2 名镶嵌父亲（9%，2/22），其中 1 名有 2 名受影响的女儿，另 1 名有 1 名受影响的孩子。两名无症状的镶嵌父亲被确认为性染色体镶嵌，MAF 分别为 4.16%-37.38%和 1.27%-19.13%。在 11 个具有明显新生变体的家族中，1 名女性患者被鉴定为镶嵌体，血液 MAF 为 26.72%。
我们的研究为 相关癫痫的表型-基因型相关性提供了新的见解，高频镶嵌突变的发现对遗传咨询具有重要意义。
