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Whole-exome sequencing analysis to identify novel potential pathogenetic NPC1 mutations in two Chinese families with Niemann–Pick disease type C

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Abstract

Background

Niemann–Pick disease type C (NPC) is an autosomal recessive lipid storage disorder, affecting the nervous system and the internal organs. It is characterized by the presence of foam cells in bone marrow, liver, and spleen biopsies. Although many mutations in NPC1 have been identified to be related to disease onset, the relationship between genotype and phenotype remains unclear. To elucidate the genetic heterogeneity of NPC, we described the clinical manifestations and possible genetic pathogenesis of two patients from unrelated families with NPC.

Methods

DNA was extracted from the peripheral blood of the two patients and their families and from healthy individuals. Whole-exome sequencing followed by Sanger sequencing was performed to verify the mutations identified in their families.

Results

We identified four mutations in NPC1 in the two patients from different families: c.1290delC (p.F431Lfs*18)/c.2807G > A(p.G936D) in family A and c.3604_3605insA (p.I1202Nfs*56)/c.881 + 3A > G in family B from their parents. Bioinformatics analysis predicted these mutations to be deleterious, suggesting that mutations in exons are highly conservative. The patient in family A presented with a developmental delay that was different from the typical symptoms of developmental regression in family B.

Conclusion

Our study identified three novel mutations and one known mutation in NPC1 and evaluated their pathogenicity, enriching the NPC1 mutation and phenotype spectrum and providing a new basis for the genetic and prenatal diagnosis of this disease.

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Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Code availability

Not available.

Abbreviations

NPC:

Niemann–Pick disease type C

WES:

Whole-exome sequencing

NP:

Niemann–Pick

VSGP:

Vertical supranuclear gaze palsy

LE:

Late endosome

GATK:

Genome Analysis Tool Kit

EEG:

Electroencephalogram

MRI:

Magnetic resonance imaging

ACMG:

American College of Medical Genetics and Genomics

LDL:

Low-density lipoprotein

HDL:

High-density lipoprotein

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Funding

This work was supported by the National Key Research and Development Program (grant numbers 2016YFC1000306), National Natural Science Foundation of China (grant numbers 30971586).

Author information

Authors and Affiliations

  1. Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China

    Chengcheng Guan & Shiguo Liu

  2. Neonatal Disease Screening Department, Zaozhuang Maternal and Child Health Hospital, Zaozhuang, China

    Xinhui Gan

  3. Pediatric Neurology Department, The Affiliated Hospital of Qingdao University, Qingdao, China

    Chengqing Yang

  4. Child Healthcare Department, The Affiliated Hospital of Qingdao University, Qingdao, China

    Mingji Yi

  5. Neuroendocrine Pediatrics Department, The Affiliated Hospital of Qingdao University, Qingdao, China

    Ying Zhang

Authors
  1. Chengcheng Guan
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  2. Xinhui Gan
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  3. Chengqing Yang
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  4. Mingji Yi
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  5. Ying Zhang
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  6. Shiguo Liu
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Contributions

Shiguo Liu designed this study; Chengcheng Guan wrote this manuscript; Xinhui Gan and Chengqing Yang collected the clinical material; Mingji Yi and Ying Zhang revised this manuscript.

Corresponding author

Correspondence to Shiguo Liu.

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The authors declare no competing interests.

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The questionnaire and methodology for this study were approved by the Human Research Ethics committee of The Affiliated Hospital of Qingdao University.

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Written informed consent was obtained from the parents.

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Patients signed informed consent regarding publishing their data and photographs.

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Cite this article

Guan, C., Gan, X., Yang, C. et al. Whole-exome sequencing analysis to identify novel potential pathogenetic NPC1 mutations in two Chinese families with Niemann–Pick disease type C. Neurol Sci 43, 3957–3966 (2022). https://doi.org/10.1007/s10072-022-05896-1

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  • DOI: https://doi.org/10.1007/s10072-022-05896-1

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