Yoon Jihoon G, Lee Seungbok, Park Soojin, Jang Se Song, Cho Jaeso, Kim Man Jin, Kim Soo Yeon, Kim Woo Joong, Lee Jin Sook, Chae Jong-Hee
Department of Genomic Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
BMC Med Genomics. 2025 Mar 3;18(1):41. doi: 10.1186/s12920-024-02058-4.
Allan-Herndon-Dudley syndrome (AHDS) is an X-linked disorder caused by pathogenic variants in the SLC16A2 gene. Although most reported variants are found in protein-coding regions or adjacent junctions, structural variations (SVs) within non-coding regions have not been previously reported.
We investigated two male siblings with severe neurodevelopmental disorders and spasticity, who had remained undiagnosed for over a decade and were negative from exome sequencing, utilizing long-read HiFi genome sequencing. We conducted a comprehensive analysis including short-tandem repeats (STRs) and SVs to identify the genetic cause in this familial case.
While coding variant and STR analyses yielded negative results, SV analysis revealed a novel hemizygous deletion in intron 1 of the SLC16A2 gene (chrX:74,460,691 - 74,463,566; 2,876 bp), inherited from their carrier mother and shared by the siblings. Determination of the breakpoints indicates that the deletion probably resulted from Alu/Alu-mediated rearrangements between homologous AluY pairs. The deleted region is predicted to include multiple transcription factor binding sites, such as Stat2, Zic1, Zic2, and FOXD3, which are crucial for the neurodevelopmental process, as well as a regulatory element including an eQTL (rs1263181) that is implicated in the tissue-specific regulation of SLC16A2 expression, notably in skeletal muscle and thyroid tissues.
This report, to our knowledge, is the first to describe a non-coding deletion associated with AHDS, demonstrating the potential utility of long-read sequencing for undiagnosed patients. Although interpreting variants in non-coding regions remains challenging, our study highlights this region as a high priority for future investigation and functional studies.
艾伦-赫恩登-达德利综合征（AHDS）是一种由SLC16A2基因的致病变异引起的X连锁疾病。尽管大多数报道的变异存在于蛋白质编码区域或相邻连接处，但非编码区域内的结构变异（SVs）此前尚未见报道。
我们利用长读长HiFi基因组测序技术，对两名患有严重神经发育障碍和痉挛的男性同胞进行了研究，他们十多年来一直未得到诊断，外显子组测序结果为阴性。我们进行了包括短串联重复序列（STRs）和SVs在内的综合分析，以确定该家族病例的遗传病因。
虽然编码变异和STR分析结果为阴性，但SV分析发现SLC16A2基因第1内含子（chrX:74,460,691 - 74,463,566；2,876 bp）存在一个新的半合子缺失，该缺失由其携带致病基因的母亲遗传而来，两名同胞均有此缺失。断点的确定表明，该缺失可能是由同源AluY对之间的Alu/Alu介导的重排导致的。预测缺失区域包含多个对神经发育过程至关重要的转录因子结合位点，如Stat2、Zic1、Zic2和FOXD3，以及一个包括eQTL（rs1263181）的调控元件，该eQTL与SLC16A2表达的组织特异性调控有关，尤其是在骨骼肌和甲状腺组织中。
据我们所知，本报告首次描述了与AHDS相关的非编码缺失，证明了长读长测序对未确诊患者的潜在用途。尽管解释非编码区域的变异仍然具有挑战性，但我们的研究强调该区域是未来研究和功能研究的高度优先领域。
