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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The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation.
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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 (2020). https://doi.org/10.1007/s10689-020-00165-6
- Fanconi anemia
- Preimplantation genetic testing
- Splicing mutations
- Minigene assay
- Functional analysis