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Clin Genet. 2019 Jul;96(1):43-52. doi: 10.1111/cge.13539. Epub 2019 Apr 3.

ATP1A3 mosaicism in families with alternating hemiplegia of childhood.

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Department of Pediatrics, Peking University First Hospital, Beijing, China.
Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
Dr Liping Wei's lab, National Institute of Biological Sciences, Beijing, China.
College of Biological Sciences, China Agricultural University, Beijing, China.
Human Genetic Resources Core Facility, School of Life Sciences, Peking University, Beijing, China.


Alternating hemiplegia of childhood (AHC) is a rare and severe neurodevelopmental disorder characterized by recurrent hemiplegic episodes. Most AHC cases are sporadic and caused by de novo ATP1A3 pathogenic variants. In this study, the aim was to identify the origin of ATP1A3 pathogenic variants in a Chinese cohort. In 105 probands including 101 sporadic and 4 familial cases, 98 patients with ATP1A3 pathogenic variants were identified, and 96.8% were confirmed as de novo. Micro-droplet digital polymerase chain reaction was applied for detecting ATP1A3 mosaicism in 80 available families. In blood samples, four asymptomatic parents, including two paternal and two maternal, and one proband with a milder phenotype were identified as mosaicism. Six (7.5%) parental mosaicisms were identified in multiple tissues, including four previously identified in blood and two additional cases identified from paternal sperms. Mosaicism was identified in multiple tissues with varied mutant allele fractions (MAFs, 0.03%-33.03%). The results suggested that MAF of mosaicism may be related to phenotype severity. This is the first systematic report of ATP1A3 mosaicism in AHC and showed mosaicism as an unrecognized source of previously considered "de novo" AHC. Identifying ATP1A3 mosaicism provides more evidence for estimating recurrence risk and has implications in genetic counseling of AHC.


ATP1A3; de novo; alternating hemiplegia of childhood; micro-droplet digital PCR; mosaicism

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