Departments of Biochemistry, Molecular Biology and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
Genes (Basel). 2023 Jan 12;14(1):196. doi: 10.3390/genes14010196.
Complex genetic disease mechanisms, such as structural or non-coding variants, currently pose a substantial difficulty in frontline diagnostic tests. They thus may account for most unsolved rare disease patients regardless of the clinical phenotype. However, the clinical diagnosis can narrow the genetic focus to just a couple of genes for patients with well-established syndromes defined by prominent physical and/or unique biochemical phenotypes, allowing deeper analyses to consider complex genetic origin. Then, clinical-diagnosis-driven genome sequencing strategies may expedite the development of testing and analytical methods to account for complex disease mechanisms as well as to advance functional assays for the confirmation of complex variants, clinical management, and the development of new therapies.
复杂的遗传疾病机制，如结构性或非编码变异，目前在一线诊断测试中构成了重大难题。因此，无论临床表型如何，它们可能是大多数未解决的罕见病患者的原因。然而，对于那些具有明显的身体和/或独特生化表型的综合征，临床诊断可以将遗传焦点缩小到几个基因，从而允许进行更深入的分析，以考虑复杂的遗传起源。然后，以临床诊断为驱动的基因组测序策略可以加快开发测试和分析方法的速度，以解决复杂的疾病机制，并推进功能测定以确认复杂的变异、临床管理和新疗法的开发。
