Lupski James, Dardas Zain, Marafi Dana, Duan Ruizhi, Fatih Jawid, El-Rashidy Omnia, Grochowski Christopher, Carvalho Claudia, Jhangiani Shalini, Bi Weimin, Du Haowei, Gibbs Richard, Posey Jennifer, Calame Daniel, Zaki Maha
Baylor College of Medicine.
Pacific Northwest Research Institute.
Res Sq. 2024 Feb 19:rs.3.rs-3949622. doi: 10.21203/rs.3.rs-3949622/v1.
Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses enabled by long read genome sequencing unveiled the presence of four distinct junctions in the father, who is carrier of a balanced CCR. The proband inherited from the father both the abnormal chromosome 5 resulting in segmental aneusomies of chr5 (loss) and chr18 (gain) and a der(2) homologue. Evidences suggest a chromoplexy mechanism for this CCR derivation, involving double-strand breaks (DSBs) repaired by non-homologous end joining (NHEJ) or alternative end joining (alt-EJ). The complexity of the CCR and the segregation of homologues elucidate the genetic model for this family. This study demonstrates the importance of combining multiple genomic technologies to uncover genetic causes of complex neurodevelopmental syndrome and to better understand genetic disease mechanisms.
尽管对神经发育障碍（NDD）的遗传基础进行了广泛研究，但许多临床病例仍未得到解决。我们研究了一名患有NDD、面部特征轻度畸形且神经影像学显示脑干发育不全的女性先证者。全面的基因组分析显示，先证者存在5号染色体末端缺失和18号染色体末端增加，而其父母的5号和18号染色体均为二倍体拷贝数。对先证者的基因组研究发现了一种不平衡易位t(5;18)，在断点处插入了来自2号染色体（2q31.3）的额外遗传物质，表明存在涉及5p15.2、2q31.3和18q21.32的复杂染色体重排（CCR）。通过长读长基因组测序进行的断点连接分析揭示了父亲（平衡CCR的携带者）中存在四个不同的连接。先证者从父亲那里继承了异常的5号染色体，导致5号染色体（缺失）和18号染色体（增加）的节段性非整倍体以及一条der(2)同源染色体。有证据表明这种CCR的产生存在一种染色体重排机制，涉及通过非同源末端连接（NHEJ）或替代末端连接（alt-EJ）修复的双链断裂（DSB）。CCR的复杂性和同源染色体的分离阐明了这个家族的遗传模式。这项研究证明了结合多种基因组技术来揭示复杂神经发育综合征的遗传原因并更好地理解遗传疾病机制的重要性。
