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Novel intronic variant in PALB2 gene and effective prevention of Fanconi anemia in family

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Abstract

Despite the acceptance of NextGen sequencing as a diagnostic modality suitable for probands and carriers of Mendelian diseases, its efficiency in identifying causal mutations is limited by both technical aspects of variant call algorithms and by imperfect, consensus-based criteria for assessing the pathogenicity of the findings. Here we describe the medical history of the family with a child born with Fanconi anemia. In this case, typical diagnostic routines were complicated by unusual combination of mutations. PALB2 variant NM_024675.3:c.172_175delTTGT (p.Gln60Argfs) in maternal sample, previously classified as a definitely pathogenic frameshift mutation, was in compound heterozygous state with PALB2 NM_024675.3:c.3114-16_3114-11del (p.Asn1039Glyfs*7), which led to validated PALB2 exon 11 skipping event in paternal locus. Findings enabled the development of the PGТ and successful selection of two mutation-free embryos. We show that even in absence of definitive exome findings, clinician-guided research inquiries into the structure and function of the suspected loci allow definitive diagnosis. Described case provides an example of a crucial input of an investigational workflow in genetic prognosis and successful PGT.

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Funding

The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation.

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Author notes

  1. I. Viakhireva, E. Musatova, E. Pomerantseva and M. Skoblov have contributed equally to this work.

Authors and Affiliations

  1. Research Centre for Medical Genetics, Moskvorechie, 1, Moscow, Russian Federation, 115522

    I. Viakhireva, E. Musatova, L. Bessonova, A. Baranova & M. Skoblov

  2. Center of Genetics and Reproductive Medicine “Genetico”, LLC, 3 b1, Gubkina str, Moscow, Russian Federation, 119333

    E. Musatova, S. Zhikriveckaya, Ya. Sofronova, I. Mironova & E. Pomerantseva

  3. Hospital Lapino, MD Medical Group, 111, 1-Ye Uspenskoye Shosse, Lapino, Moskovskaya region, Russian Federation, 143081

    Y. Shcherbatyuk & S. Korobkov

  4. Genomed, Ltd, 8 b5, Podol’skoye Shosse, Moscow, Russian Federation, 115093

    D. Khmelkova & F. Konovalov

  5. Chronic Metabolic and Rare Diseases Systems Biology Initiative (ChroMe RaDSBIn), School of Systems Biology, George Mason University, 4400 University Dr, Fairfax, VA, 22030, USA

    A. Baranova

Authors
  1. I. Viakhireva
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  2. E. Musatova
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  3. L. Bessonova
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  4. Y. Shcherbatyuk
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  5. S. Korobkov
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  6. S. Zhikriveckaya
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  7. Ya. Sofronova
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  8. I. Mironova
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  9. D. Khmelkova
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  10. F. Konovalov
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  11. A. Baranova
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  12. E. Pomerantseva
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  13. M. Skoblov
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Corresponding author

Correspondence to M. Skoblov.

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All authors declare that they have no conflict of interest.

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Viakhireva, I., Musatova, E., Bessonova, L. et al. Novel intronic variant in PALB2 gene and effective prevention of Fanconi anemia in family. Familial Cancer 19, 241–246 (2020). https://doi.org/10.1007/s10689-020-00165-6

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  • DOI: https://doi.org/10.1007/s10689-020-00165-6

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