New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases

Abstract

Accurate diagnosis is the cornerstone of medicine; it is essential for informed care and promoting patient and family well-being. However, families with a rare genetic disease (RGD) often spend more than five years on a diagnostic odyssey of specialist visits and invasive testing that is lengthy, costly, and often futile, as 50% of patients do not receive a molecular diagnosis. The current diagnostic paradigm is not well designed for RGDs, especially for patients who remain undiagnosed after the initial set of investigations, and thus requires an expansion of approaches in the clinic. Leveraging opportunities to participate in research programs that utilize new technologies to understand RGDs is an important path forward for patients seeking a diagnosis. Given recent advancements in such technologies and international initiatives, the prospect of identifying a molecular diagnosis for all patients with RGDs has never been so attainable, but achieving this goal will require global cooperation at an unprecedented scale. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 21 is August 31, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

How to design a registry for undiagnosed patients in the framework of rare disease diagnosis – suggestions on software, data set and coding system

“…In case of a diagnostic impasse all available investigations have been carried out by experts and the patient and physicians may be facing a new, yet undescribed disorder. (11,16,17) Implications for Physicians Due to the large number of rare diseases, it is impossible for a single doctor to be familiar with all of them. Especially general practitioners, who are the rst contact for many patients, feel insu ciently trained in detecting rare diseases and often lack close interdisciplinary collaboration.…”

“…(9,10) The diagnostic odyssey, that many patients affected by rare diseases experience, is often due to multiple causes: a non-speci c clinical presentation involving multiple organ systems that seem to be unrelated, a general lack of awareness and physician training regarding rare diseases, missing standard diagnostic criteria, a limited number of specialists, uncoordinated patient journeys through the health-care system, that cause loss of information and increase the possibility of errors and sometimes limited access to diagnostic tools. (11)(12)(13) The connection between undiagnosed and rare disease patients It is important to state, that rare diseases remain not always undiagnosed and undiagnosed diseases are not always hidden rare diseases. The undiagnosed patient can be affected by a rare disease, a more common disease that presents atypically, by multiple diseases occurring simultaneously, including psychosomatic disorders or by a completely new and uncharacterized disease.…”

“…This can be caused by gatekeeping delays in primary care due to missing knowledge about rare diseases as well as systemic problems due to a lack of coordination, collaboration and adequate exchange of information between several healthcare providers. (11,(15)(16)(17) A complex diagnosis is de ned by a non-conclusive phenotype and genomic pro le, insu cient biomarkers, presentation of unspeci c but common symptoms or the concurrent existence of more than one disease. In this case, the patient might require speci c equipment and contact with a centre of expertise or a reference network.…”

“…In case of a diagnostic impasse all available investigations have been carried out by experts and the patient and physicians may be facing a new, yet undescribed disorder. (11,16,17)…”

Association between HindIII (rs320) variant in the lipoprotein lipase gene and the presence of coronary artery disease and stroke among the Saudi population

“…Several case-control and meta -analysis studies have shown the relation between LPL gene and CAD ( Xu et al, 2019 , Javorsky et al, 2007 , Daoud et al, 2013 , Fischer et al, 2018 , Ma et al, 2018 , Shahid et al, 2017 , Xie, 2017 ). The accurate genetic and molecular or any other mechanism which affects the LPL and human disease is poorly understood and LDL was interrelated towards certain heterogenous disorders which involve limited cardiovascular disorders ( Hartley et al, 2020 ). The rs320 polymorphism has been studied globally in CAD, stroke, dyslipidemia ( Javorsky et al, 2007 , Nejati et al, 2018 , Sagoo et al, 2008 , Samgina et al, 2016 , Tetik Vardarli et al, 2017 , Velasquez Pereira et al, 2016 ) and this polymorphism is located between the intron 6–8 and important role of rs320 polymorphism could elevate the atherosclerosis risk through influencing plasma lipid levels ( Nagrani et al, 2020 ).…”