A long-read genome sequencing approach to identify novel genes associated with accelerated aging phenotypes

Hallermann-Streiff综合征（HSS; OMIM 234100）是一种众所周知的罕见先天性综合征，其特征在于颅面畸形、身材矮小、眼部畸形以及皮肤和毛发异常以及独特的面部外观。其遗传基础和潜在的分子机制至今尚未被揭示。HSS属于加速老化或早衰综合征组，其概括了非常早期的生理老化和老化相关病理的标志性特征。因此，早老性综合征中致病基因的鉴定也提供了一个非常强大的工具，以调查和阐明衰老的生物学过程，并获得新的见解与衰老相关的疾病，如心血管疾病，癌症或神经变性的发展。多种早老性综合征已归因于细胞和分子机制的缺陷，所述细胞和分子机制也与生理老化和老化相关疾病相关，并且其遗传基础已被鉴定为影响例如染色质结构、基因组稳定性、转录控制、DNA损伤修复、核组织或表观遗传调节的突变。在初步研究中，我们已经应用了各种下一代测序（NGS）方法。我们确定了四个有前途的候选基因，我们的初步功能分析的结果表明，他们编码的蛋白质的行为在一个共同的机制，参与染色质相关的过程和转录控制。尽管如此，我们使用短读全外显子组测序（WES）和全基因组测序（WGS）策略进行的广泛基因鉴定研究显示，仅在一小部分HSS患者中发现了致病突变。因此，在下一个合乎逻辑的步骤中，我们的目标是使用PacBio技术对我们的HSS患者队列应用长读WGS，以揭示特定的突变谱（例如较大的缺失，重复或倒位），这在短读测序方法中无法检测到。为了解释从生成的PacBio NGS数据集中识别的结构畸变以及单核苷酸变异，我们将得到哥廷根人类遗传学研究所MutationMining（MM）团队的专业知识和经验的支持。新突变和基因的鉴定将使我们能够更深入地了解HSS和加速衰老发病机制中涉及的遗传机制和细胞过程。这些知识也将提高我们对生理衰老和衰老相关病理学的理解。

Hallermann-Streiff syndrome (HSS; OMIM 234100) is a well-known, rare congenital syndrome, characterized by craniofacial dysmorphism, short stature, eye malformations as well as anomalies of skin and hair, and a distinctive facial appearance. Its genetic basis and underlying molecular mechanism have so far not been unveiled. HSS belongs to the group of accelerated-aging or progeroid syndromes, which recapitulate hallmark features of physiological aging and aging-associated pathologies at a very early age. Identification of disease-causing genes in progeroid syndromes thus also provides a very powerful tool to investigate and elucidate the biological processes of aging and to gain new insights into the development of aging-related diseases like cardiovascular disease, cancer or neurodegeneration. A variety of progeroid syndromes have been attributed to defects in cellular and molecular mechanisms that are also relevant in physiological aging and in aging-associated disease and their genetic basis has been identified as mutations affecting e.g. chromatin structure, genome stability, transcriptional control, DNA damage repair, nuclear organization or epigenetic regulation.We have collected a unique cohort of > 30 patients with HSS, and in preliminary studies, we have already applied various next-generations sequencing (NGS) approaches. We identified four promising candidate genes and the results of our initial functional analyses suggest that their encoded proteins act in a common mechanism involved in chromatin-related processes and transcriptional control. Still, our extensive gene identification studies using short-read whole-exome sequencing (WES) and whole-genome sequencing (WGS) strategies revealed causative mutations only in a small proportion of our HSS patients. In a next, logical step, we therefore aim at applying long-read WGS using the PacBio technology on our cohort of HSS patients to uncover specific mutation profiles (such as e.g. larger deletions, duplications, or inversions), which could not be detected in a short-read sequencing approach. For interpretation of identified structural aberrations as well as single nucleotide variants from the generated PacBio NGS data sets, we will be supported by the expertise and experience of the MutationMining (MM) team at the Institute of Human Genetics in Göttingen. Identification of novel mutations and genes will allow us to gain deeper insights into the genetic mechanisms and cellular processes that are involved in the pathogenesis of HSS and accelerated aging. Such knowledge will also improve our understanding of physiological aging and aging-associated pathologies.