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A novel KRIT1/CCM1 mutation accompanied by a NOTCH3 mutation in a Chinese family with multiple cerebral cavernous malformations

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Abstract

Family cerebral cavernous malformations (FCCMs) are mainly inherited through the mutation of classical CCM genes, including CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. FCCMs can cause severe clinical symptoms, including epileptic seizures, intracranial hemorrhage (ICH), or functional neurological deficits (FNDs). In this study, we reported a novel mutation in KRIT1 accompanied by a NOTCH3 mutation in a Chinese family. This family consists of 8 members, 4 of whom had been diagnosed with CCMs using cerebral MRI (T1WI, T2WI, SWI). The proband (II-2) and her daughter (III-4) had intracerebral hemorrhage and refractory epilepsy, respectively. Based on whole-exome sequencing (WES) data and bioinformatics analysis from 4 patients with multiple CCMs and 2 normal first-degree relatives, a novel KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in intron 13 was considered a pathogenic gene in this family. Furthermore, based on 2 severe and 2 mild CCM patients, we found an SNV missense mutation, NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C), in NOTCH3. Finally, the KRIT1 and NOTCH3 mutations were validated in 8 members using Sanger sequencing. This study revealed a novel KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in a Chinese CCM family, which had not been reported previously. Moreover, the NOTCH3 mutation NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C) might be a second hit and associated with the progression of CCM lesions and severe clinical symptoms.

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Data availability

The datasets used and/or analyzed during the current work are available from the corresponding author on reasonable request.

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Funding

This study was supported by a Fujian Clinical Research Center for Neurological Diseases (principal investigator: Professor Dezhi Kang), a grant from Fujian Provincial Department of Science and Technology (Grant number: 2020Y2003), and also supported by National Natural Science Fund (No. 81870930 and No. 82171327, principal investigator: Dezhi Kang) grant from the National Natural Science Foundation of China.

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Author notes

  1. Chunwang Li, Penghui Liu, and Weilin Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China

    Chunwang Li, Penghui Liu, Haojie Wang, Lingyun Zhuo, Qiu He, Yuanxiang Lin, Dezhi Kang & Fuxin Lin

  2. Department of Neurosurgery, Binhai Branch of National Regional Medical Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350209, Fujian, China

    Chunwang Li, Penghui Liu, Haojie Wang, Qiu He, Yuanxiang Lin, Dezhi Kang & Fuxin Lin

  3. Department of Radiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China

    Weilin Huang & Yaqing Kang

  4. Clinical Research and Translation Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China

    Ke Ma, Dezhi Kang & Fuxin Lin

  5. Fujian Provincial Institutes of Brain Disorders and Brain Sciences, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China

    Yuanxiang Lin, Dezhi Kang & Fuxin Lin

  6. Fujian Provincial Clinical Research Center for Neurological Diseases, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China

    Yuanxiang Lin, Dezhi Kang & Fuxin Lin

  7. Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China

    Dezhi Kang

Authors
  1. Chunwang Li
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  2. Penghui Liu
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  8. Qiu He
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  9. Yuanxiang Lin
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  10. Dezhi Kang
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Contributions

Conceptualization: D.Z.K., Y.X.L., and F.X.L.; subjects collection: H.J.W., L.Y.Z., and Q.H.; Brain MRI scan and diagnosis: W.L.H. and Y.Q.K.; analysis of data and bioinformatics: C.W.L. and P.H.L.; writing—original draft and figure preparation: C.W.L. and P.H.L.; review and editing: F.X.L.; supervision: D.Z.K., Y.X.L., and F.X.L.

Corresponding authors

Correspondence to Dezhi Kang or Fuxin Lin.

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Li, C., Liu, P., Huang, W. et al. A novel KRIT1/CCM1 mutation accompanied by a NOTCH3 mutation in a Chinese family with multiple cerebral cavernous malformations. Neurogenetics 24, 137–146 (2023). https://doi.org/10.1007/s10048-023-00714-y

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