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

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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.