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.

中文翻译：

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PALB2基因的新型内含子变异体，可有效预防家庭中的范科尼贫血。

尽管NextGen测序已被接受为适用于孟德尔疾病先证者和携带者的诊断方法，但其识别因果突变的效率受到变异调用算法的技术方面以及评估结果的致病性的基于共识的不完善标准的限制。 。在这里，我们描述了一个患有Fanconi贫血的孩子的家庭病史。在这种情况下，典型的诊断程序会因异常的突变组合而变得复杂。母体样品中的PALB2变体NM_024675.3：c.172_175delTTGT（p.Gln60Argfs），先前被归类为绝对致病的移码突变，与PALB2处于复合杂合状态NM_024675.3：c.3114-16_3114-11del（p.Asn1039Glyfs * 7），这导致在父本位点验证了PALB2外显子11跳跃事件。这些发现使PGТ得以发展，并成功选择了两个无突变的胚胎。我们表明，即使在没有明确的外显子组发现的情况下，由临床医生指导的对可疑基因座的结构和功能的研究查询也可以进行明确的诊断。所述病例提供了遗传预后和成功PGT中研究工作流程的关键输入的实例。