Table1_Whole genome sequencing in ROHHAD trios proved inconclusive: what’s beyond?.xlsx

Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a rare, life-threatening, pediatric disorder of unknown etiology, whose diagnosis is made difficult by poor knowledge of clinical manifestation, and lack of any confirmatory tests. Children with ROHHAD usually present with rapid onset weight gain which may be followed, over months or years, by hypothalamic dysfunction, hypoventilation, autonomic dysfunction, including impaired bowel motility, and tumors of neural crest origin. Despite the lack of evidence of inheritance in ROHHAD, several studies have been conducted in recent years that have explored possible genetic origins, with unsuccessful results. In order to broaden the search for possible genetic risk factors, an attempt was made to analyse the non-coding variants in two trios (proband with parents), recruited in the Gaslini Children’s Hospital in Genoa (Italy). Both patients were females, with a typical history of ROHHAD. Gene variants (single nucleotide variants, short insertions/deletions, splice variants or in tandem expansion of homopolymeric tracts) or altered genomic regions (copy number variations or structural variants) shared between the two probands were searched. Currently, we have not found any potentially pathogenic changes, consistent with the ROHHAD clinical phenotype, and involving genes, regions or pathways shared between the two trios. To definitively rule out the genetic etiology, third-generation sequencing technologies (e.g., long-reads sequencing, optical mapping) should be applied, as well as other pathways, including those associated with immunological and autoimmune disorders, should be explored, making use not only of genomics but also of different -omic datasets.

下丘脑功能障碍、低通气与自主神经失调性快速起病肥胖（Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation，ROHHAD）是一种病因不明的罕见、危及生命的儿科疾病，由于临床认知不足且缺乏确认性检测手段，其诊断颇具难度。ROHHAD患儿通常先出现快速体重增加，随后在数月至数年内相继出现下丘脑功能障碍、低通气、自主神经功能异常（包括肠道动力受损）以及神经嵴源性肿瘤。尽管目前尚无ROHHAD存在遗传倾向的证据，但近年已有多项研究探索其潜在遗传起源，均未获得阳性结果。为拓宽潜在遗传风险因子的搜索范围，本研究对招募自意大利热那亚加斯利尼儿童医院的两个三人家系（先证者（proband）及其双亲）的非编码变异（non-coding variants）进行了分析。两名受试者均为女性，具备典型的ROHHAD病史。研究旨在筛选两名先证者共有的基因变异，包括单核苷酸变异（single nucleotide variants）、短插入/缺失（short insertions/deletions）、剪接变异（splice variants）或同源多聚核苷酸序列的串联扩增（in tandem expansion of homopolymeric tracts），以及共有的基因组区域改变，包括拷贝数变异（copy number variations）或结构变异（structural variants）。截至目前，本研究尚未发现与ROHHAD临床表型相符、且累及两个家系共有的基因、区域或通路的潜在致病性改变。为明确排除遗传病因，需应用第三代测序技术（third-generation sequencing technologies），例如长读长测序（long-reads sequencing）、光学图谱（optical mapping），同时还应探索其他通路，包括与免疫及自身免疫性疾病相关的通路，研究手段不仅需涵盖基因组学，还应整合不同类型的组学数据集（-omic datasets）。