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Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome

Journal of Human Genetics volume 65, pages 911–915 (2020)Cite this article

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Abstract

Two variants in the ubiquitously expressed NHLRC2 gene have been reported to cause a lethal fibrotic cerebropulmonary disease termed fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome in three Finnish children. Our objective was to determine the genetic basis of disease in a new patient with clinical features of FINCA syndrome using whole-exome sequencing (WES) and confirmation by Sanger sequencing. The patient has one known and one novel variant in NHLRC2 (c.442T>G, p.D148Y and c.428C>A, p.H143P, respectively). p.H143P is extremely rare and is not present in the gnomAD database of >140,000 allele sequences from healthy humans. Both variants affect the highly conserved N-terminal thioredoxin (Trx)-like domain of NHLRC2 and are predicted to be damaging. We conclude that a compound heterozygous combination of a known and a novel variant in NHLRC2 causes FINCA syndrome in a 2-year-old Ukrainian patient, underscoring the importance of NHLRC2 as a central regulator of fibrosis.

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References

  1. Biterova E, Ignatyev A, Uusimaa J, Hinttala R, Ruddock LW. Structural analysis of human NHLRC2, mutations of which are associated with FINCA disease. PLoS One. 2018;13:e0202391.

    Article  CAS  Google Scholar 

  2. Uusimaa J, Kaarteenaho R, Paakkola T, Tuominen H, Karjalainen MK, Nadaf J, et al. NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease. Acta Neuropathol. 2018;135:727–42.

    Article  CAS  Google Scholar 

  3. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. bioRxiv. 2019:531210.

  4. Nishi K, Iwaihara Y, Tsunoda T, Doi K, Sakata T, Shirasawa S, et al. ROS-induced cleavage of NHLRC2 by caspase-8 leads to apoptotic cell death in the HCT116 human colon cancer cell line. Cell Death Dis. 2017;8:3218.

    Article  CAS  Google Scholar 

  5. Paakkola T, Salokas K, Miinalainen I, Lehtonen S, Manninen A, Kaakinen M, et al. Biallelic mutations in human NHLRC2 enhance myofibroblast differentiation in FINCA disease. Hum Mol Genet. 2018;27:4288–302.

    PubMed  CAS  Google Scholar 

  6. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5.

    Article  CAS  Google Scholar 

  7. Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47:D886–D94.

    Article  CAS  Google Scholar 

  8. Boyarchuk O, Volokha A, Hariyan T, Kinash M, Volyanska L, Birchenko I, et al. The impact of combining educational program with the improving of infrastructure to diagnose on early detection of primary immunodeficiencies in children. Immunol Res. 2019;67:390–7.

    Article  Google Scholar 

  9. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.

    Article  CAS  Google Scholar 

  10. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the family for their participation in our study. We also acknowledge Monica Konstantino, BSN, and MSN, for her support.

Funding

This work was supported by Yale University, Yale Medicine, the Immune Deficiency Foundation, and the Hood Foundation.

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Author notes

  1. These authors contributed equally: Nina N. Brodsky, Oksana Boyarchuk

Authors and Affiliations

  1. Yale University Department of Immunobiology, New Haven, CT, USA

    Nina N. Brodsky, Andrew Rice & Carrie L. Lucas

  2. Yale University Department of Pediatrics, New Haven, CT, USA

    Nina N. Brodsky, Weizhen Ji, Mustafa Khokha & Saquib Lakhani

  3. Horbachevsky Ternopil National Medical University, Department of Children’s Diseases and Pediatric Surgery, Ternopil, Ukraine

    Oksana Boyarchuk, Tetyana Kovalchuk & Tetyana Hariyan

  4. Yale University Pediatric Genomics Discovery Program, New Haven, CT, USA

    Weizhen Ji, Mustafa Khokha, Saquib Lakhani & Carrie L. Lucas

Authors
  1. Nina N. Brodsky
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  2. Oksana Boyarchuk
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  3. Tetyana Kovalchuk
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  4. Tetyana Hariyan
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  5. Andrew Rice
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  6. Weizhen Ji
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  7. Mustafa Khokha
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  9. Carrie L. Lucas
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Contributions

NNB analyzed and reviewed clinical and genetic data and wrote the manuscript. OB cared for the patient, reviewed data, and wrote the manuscript. TK and TH assisted in caring for the patient. AR provided technical assistance. WJ, MK, and SL analyzed and reviewed genetic data. CLL organized enrollment in genomic protocol, analyzed and reviewed all data, and wrote the manuscript. All authors approved the manuscript.

Corresponding authors

Correspondence to Oksana Boyarchuk or Carrie L. Lucas.

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The authors declare that they have no conflict of interest.

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Brodsky, N.N., Boyarchuk, O., Kovalchuk, T. et al. Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome. J Hum Genet 65, 911–915 (2020). https://doi.org/10.1038/s10038-020-0776-0

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  • DOI: https://doi.org/10.1038/s10038-020-0776-0

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