Moch Johanna, Radtke Maximilian, Gburek-Augustat Janina, Karnstedt Maike, Schönnagel Senta, Drukewitz Stephan H, Pilgram Laura, Hentschel Julia, Schumann Isabell
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Division of Neuropaediatrics, Hospital for Children and Adolescents, University of Leipzig Medical Center, Leipzig, Germany.
Front Genet. 2023 Dec 21;14:1297754. doi: 10.3389/fgene.2023.1297754. eCollection 2023.
Uniparental disomy (UPD) is the inheritance of both alleles of a chromosome from only one parent. So far, the detection of UPDs in sequencing data is not well established and a known gap in next-generation sequencing (NGS) diagnostics. By developing a new tool for UPD detection, we re-evaluated an eight-year-old individual presenting with scoliosis, muscle weakness and global developmental delay. Previous panel analysis identified a homozygous likely pathogenic loss-of-function variant in the -gene associated with arthrogryposis (OMIM # 617146). Interestingly, during a re-evaluation process, we identified a region of homozygosity (ROH) covering over 95% of chromosome 18. Segregation and microsatellite analysis within the family revealed that only the father is a heterozygous carrier of the variant in and confirmed paternal uniparental isodisomy (iUPD) on chromosome 18 in the individual. Further methylation analysis indicated demethylation of the promotor region of , which is described to be maternally imprinted and could possibly influence the individuals' phenotype. Our report describes the first complete iUPD on chromosome 18 and highlights that UPDs can be a cause for homozygous pathogenic variants, which reduces the risk of reoccurrence in case of a new pregnancy in comparison to an autosomal recessive inheritance trait significantly.
单亲二体性（UPD）是指一条染色体的两个等位基因均仅从一个亲本遗传而来。到目前为止，在测序数据中检测UPD的方法尚未完善，这是下一代测序（NGS）诊断中一个已知的空白。通过开发一种用于检测UPD的新工具，我们重新评估了一名患有脊柱侧弯、肌肉无力和全面发育迟缓的8岁个体。之前的基因检测板分析在与关节挛缩相关的基因（OMIM # 617146）中鉴定出一个纯合的可能致病的功能丧失变异。有趣的是，在重新评估过程中，我们发现了一个覆盖超过95%的18号染色体的纯合区域（ROH）。对该家族进行的分离分析和微卫星分析显示，只有父亲是该基因变异的杂合携带者，并证实该个体18号染色体存在父源单亲同二体性（iUPD）。进一步的甲基化分析表明该基因启动子区域的去甲基化，该区域被描述为母源印记，可能会影响个体的表型。我们的报告描述了首例完整的18号染色体iUPD，并强调UPD可能是纯合致病变异的一个原因，与常染色体隐性遗传性状相比，这显著降低了再次怀孕时复发的风险。
