Zhou Amy, Rand Casey M, Hockney Sara M, Niewijk Grace, Reineke Patrick, Speare Virginia, Berry-Kravis Elizabeth M, Zhou Lili, Jennings Lawrence J, Yu Min, Ceccherini Isabella, Bachetti Tiziana, Pennock Melanie, Yap Kai Lee, Weese-Mayer Debra E
Department of Pediatrics, Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children's Hospital of Chicago and Stanley Manne Children's Research Institute, Chicago, IL, USA.
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Genet Med. 2021 Sep;23(9):1656-1663. doi: 10.1038/s41436-021-01178-x. Epub 2021 May 6.
CCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype-phenotype correlation has not been established. This comprehensive report of PHOX2B NPARMs and associated phenotypes, aims at elucidating potential genotype-phenotype correlations that will guide anticipatory management.
An international collaboration (clinical, commercial, and research laboratories) was established to collect/share information on novel and previously published PHOX2B NPARM cases. Variants were categorized by type and gene location. Categorical data were analyzed with chi-square and Fisher's exact test; further pairwise comparisons were made on significant results.
Three hundred two individuals with PHOX2B NPARMs were identified, including 139 previously unreported cases. Findings demonstrate significant associations between key phenotypic manifestations of CCHS and variant type, location, and predicted effect on protein function.
This study presents the largest cohort of PHOX2B NPARMs and associated phenotype data to date, enabling genotype-phenotype studies that will advance personalized, anticipatory management and help elucidate pathological mechanisms. Further characterization of PHOX2B NPARMs demands longitudinal clinical follow-up through international registries.
先天性中枢性低通气综合征（CCHS）是一种极其罕见的先天性疾病，需要人工通气来维持生命。通常由PHOX2B基因中的杂合聚丙氨酸重复扩增突变（PARMs）引起，确定PARMs长度与表型严重程度之间的关系有助于进行预期管理。然而，对于PHOX2B基因中存在非PARMs（NPARMs，约占CCHS患者的10%）的患者，尚未建立基因型-表型相关性。这份关于PHOX2B NPARMs及其相关表型的综合报告旨在阐明潜在的基因型-表型相关性，以指导预期管理。
建立了一个国际合作项目（临床、商业和研究实验室），以收集/分享有关新的和先前发表的PHOX2B NPARM病例的信息。变异体按类型和基因位置进行分类。分类数据采用卡方检验和Fisher精确检验进行分析；对显著结果进行进一步的两两比较。
共鉴定出302例携带PHOX2B NPARMs的个体，其中包括139例先前未报告的病例。研究结果表明，CCHS的关键表型表现与变异体类型、位置以及对蛋白质功能的预测影响之间存在显著关联。
本研究提供了迄今为止最大规模的PHOX2B NPARMs队列及其相关表型数据，使基因型-表型研究得以推进，从而实现个性化的预期管理，并有助于阐明病理机制。对PHOX2B NPARMs的进一步特征描述需要通过国际登记处进行纵向临床随访。
