PACS gene family-related neurological diseases:limited genotypes and diverse phenotypes

Han Zhang ¹Kai Gao ²Shuang Wang ¹Yue-Hua Zhang ¹Zhi-Xian Yang ¹Ye Wu ¹Yu-Wu Jiang³

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作者信息

1. Department of Pediatrics,Peking University First Hospital,No.1 Xi'an Men Street,West District,Beijing 100034,China;Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases,Beijing,China;Children Epilepsy Center,Peking University First Hospital,Beijing,China
2. Department of Pediatrics,Peking University First Hospital,No.1 Xi'an Men Street,West District,Beijing 100034,China;Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases,Beijing,China;Children Epilepsy Center,Peking University First Hospital,Beijing,China;Key Laboratory for Neuroscience,Ministry of Education/National Health and Family Planning Commission,Peking University,Beijing,China
3. Department of Pediatrics,Peking University First Hospital,No.1 Xi'an Men Street,West District,Beijing 100034,China;Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases,Beijing,China;Children Epilepsy Center,Peking University First Hospital,Beijing,China;Key Laboratory for Neuroscience,Ministry of Education/National Health and Family Planning Commission,Peking University,Beijing,China;Center of Epilepsy,Beijing Institute for Brain Disorders,Beijing,China
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Abstract

Background The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking.The phenotypic manifestations caused by the pathogenic variants of PACS include epilepsy,intellectual disability/developmental delay,and malformations,such as facial abnormalities.Methods We identified seven new cases with pathogenic or likely pathogenic PACS variants using next-generation sequenc-ing.Detailed information obtained from these patients was analyzed along with that obtained from previously reported patients.Results With the inclusion of the newly diagnosed cases in this study,103 cases with PACS gene family-related neurological diseases were reported,of which 43 were PACS2-related cases and the remaining were PACS1-related cases.Most patients had seizures,which have been reported to be effectively controlled by several types of anti-seizure medications(ASMs).The most efficacious and frequently prescribed ASMs included sodium valproate(43.3％,13/30),oxcarbazepine/carbamazepine(26.7％,8/30),and levetiracetam(20％,6/30).Almost all patients had intellectual disability/developmental delay.The most common pathogenic missense variants were PACS1 p.Arg203Trp and PACS2 p.Glu209Lys.In addition,we report a patient carrying a likely pathogenic copy number variation(CNV)(de novo heterozygous deletion of chrl4:105821380-106107443,286 kilobase,destroyed part of the furin-binding region domain and the protein structure after it)with more severe and refractory late-onset epilepsy.Conclusions The clinical phenotypes of the different PACS heterozygous missense variants were similar.The pathogenic variant sites of PACS1 and PACS2 were quite limited but located in different regions.A CNV destroying part of the PACS2 gene might also be pathogenic.These findings may provide an important clue for further functional studies on the pathogenic mechanism of neurological disorders related to the PACS gene family.

Key words

Developmental delay/Epilepsy/Intellectual disability/PACS1/PACS2

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基金项目

National Key Research and Development Program of China(2020YFA0804000)

National Natural Science Foundation of China(81971211)

National Natural Science Foundation of China(12026606)

National Natural Science Foundation of China(81601131)

Key Project of Clinical Medicine Research of National Clinical Research Center for Child Health and Disorders,Children's Hospita(NCRCCHD-2021-KP-02)

Beijing Natural Science Foundation(7212109)

Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(BZ0317)

Capital Health Research and Development of Special Fund(2020-1-4071)

National High Level Hospital Clinical Research Funding(Scientific Research Seed Fund of Peking University First Hospital)(2022SF29)

Fundamental Research Funds for the Central Universities(BMU2017JI002)

Fundamental Research Funds for the Central Universities(BMU2018XY006)

Fundamental Research Funds for the Central Universities(PKU2017LCX06)

出版年

2024

世界儿科杂志(英文版)

CSTPCD

ISSN：

参考文献量22

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