Vieira Daniela Koeller R, Lima Ingrid Bendas Feres, Rosenberg Carla, Fonseca Carlos Roberto da, Gomes Leonardo Henrique Ferreira, Guida Letícia da Cunha, Mazzonetto Patrícia Camacho, Llerena Juan, Bastos Elenice Ferreira
Centro de Genética Médica, Instituto Nacional da Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira-Fundação Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil.
Secretaria Municipal de Saúde de Angra dos Reis, Angra dos Reis 23906-010, Brazil.
Genes (Basel). 2024 Nov 29;15(12):1546. doi: 10.3390/genes15121546.
Balanced chromosomal translocations occur in approximately 0.16 to 0.20% of live births. While most carriers are phenotypically normal, they are at risk of generating unbalanced gametes during meiosis, leading to genetic anomalies such as aneuploidies, deletions, duplications, and gene disruptions. These anomalies can result in spontaneous abortions or congenital anomalies, including neurodevelopmental disorders. Complex chromosomal rearrangements (CCRs) involving more than two chromosomes are rare but further increase the probability of producing unbalanced gametes. Neurodevelopmental disorders such as Angelman syndrome (AS) and duplication 15q11q13 syndrome (Dup15q) are associated with such chromosomal abnormalities.
This study describes a family with a de novo maternal balanced double translocation involving chromosomes 13, 19, and 15, resulting in two offspring with unbalanced chromosomal abnormalities. Cytogenetic evaluations were performed using GTG banding, fluorescence in situ hybridization (FISH), and low-pass whole-genome sequencing (LP-WGS). Methylation analysis was conducted using methylation-sensitive high-resolution melting (MS-HRM) to diagnose Angelman syndrome.
The cytogenetic and molecular analyses identified an 8.9 Mb duplication in 15q11.2q13.3 in one child, and an 8.9 Mb deletion in the same region in the second child. Both abnormalities affected critical neurodevelopmental genes, such as . FISH and MS-HRM confirmed the chromosomal imbalances and the diagnosis of Angelman syndrome in the second child. The maternal balanced translocation was found to be cryptic, contributing to the complex inheritance pattern.
This case highlights the importance of using multiple genetic platforms to uncover complex chromosomal rearrangements and their impact on neurodevelopmental disorders. The findings underscore the need for thorough genetic counseling, especially in families with such rare chromosomal alterations, to manage reproductive outcomes and neurodevelopmental risks.
平衡染色体易位发生在约0.16%至0.20%的活产儿中。虽然大多数携带者表型正常，但他们在减数分裂期间有产生不平衡配子的风险，从而导致非整倍体、缺失、重复和基因破坏等遗传异常。这些异常可导致自然流产或先天性异常，包括神经发育障碍。涉及两条以上染色体的复杂染色体重排（CCR）很少见，但会进一步增加产生不平衡配子的概率。诸如天使综合征（AS）和15q11q13重复综合征（Dup15q）等神经发育障碍与此类染色体异常有关。
本研究描述了一个家庭，母亲发生了涉及13号、19号和15号染色体的新生平衡双易位，导致两个后代出现染色体不平衡异常。使用GTG显带、荧光原位杂交（FISH）和低通全基因组测序（LP-WGS）进行细胞遗传学评估。使用甲基化敏感高分辨率熔解（MS-HRM）进行甲基化分析以诊断天使综合征。
细胞遗传学和分子分析发现，一个孩子的15q11.2q13.3区域有8.9 Mb的重复，另一个孩子的同一区域有8.9 Mb的缺失。这两种异常都影响了关键的神经发育基因，如。FISH和MS-HRM证实了第二个孩子的染色体不平衡以及天使综合征的诊断。发现母亲的平衡易位是隐匿性的，导致了复杂的遗传模式。
本病例强调了使用多种遗传平台来揭示复杂染色体重排及其对神经发育障碍影响的重要性。研究结果强调了进行全面遗传咨询的必要性，特别是在有此类罕见染色体改变的家庭中，以管理生殖结局和神经发育风险。
