Mice carrying this mutation presented neurological disease, suggesting importance of substrate specificity of flipperse (JCI, 2021 131:e148005). In a patient with neurological deterioration, we detected a de novo ATP11A missense mutation, which made ATP11A to flip phosphatidylcholine as well as phosphatidylserine. ATP11A translocates phosphatidylserine, but not phosphatidylcholine, from the outer to the inner leaflet of plasma membrane. The third disease is an abnormal metabolism of phospholipid. We made lens- and skin-specific Lss knockout mice and found that they showed cataract or hypotrichosis, suggesting that these phenotypes are allelic (PLos Genet, 2020 16:e1008628, MIM#618840). LSS mutations were reported only in patients with congenital cataract. Compound heterozygous LSS mutations was identified in a sib with congenital hypotrichosis and accumulation of epoxysqualene in sebum. The second disease is caused by abnormal cholesterol metabolism by deficiency of LSS, which converts epoxysqualene to lanosterol. This new type of galactosemia is named as type IV (Genet Med, 2019 6:1286, MIM#618443). Eight patients with undiagnosed galactosemia were identified to have no mutations in any of these genes, but have GALM mutations, which catalyzes epimerization of galactose. Types I, II and III of classical galactosemia were caused by GALT, GALK1 and GALE mutations, respectively.
The first disease is a novel inborn error of galactose metabolism. In IRUD we encountered three new metabolic disorders. As a clinical/analytical center of IRUD we have analyzed ~300 undiagnosed families by whole exome and/or genome sequencing, with diagnosis rate of ~45%. Initiative on Rare and Undiagnosed disease (IRUD) has started in Japan for 7 years. O-2 New disorders discovered by whole genome sequencingġ Department of Pediatrics, Tohoku University Graduate School of Medicine The UDP also supports an International Undiagnosed Diseases Network that has recently added Working Groups for Developing Nations and Diagnostics and will hold its 10th international conference in Torino, Italy, in early February of 2022. Functional studies are performed via granting mechanisms, all through the NIH's Common Fund in the Office of the NIH Director. From 2015-21, the UDN reviewed 5000 applications, evaluated more than 1500 patients, and made more than 460 diagnoses. The UDP has expanded into an Undiagnosed Diseases Network (UDN) of 12 clinical sites (including the NIH UDP) throughout the United States, a Coordinating Center, a Sequencing Core, Model Organisms Screening Cores, a Metabolomics Core, and a Biorepository.
Some rare and novel diagnoses have led to treatments, such as anakinra for a gain-of-function mutation in NLRP3 causing recurrent aseptic meningitis and deep brain stimulation for dystonia due to a KMT2B mutation. Examples include vascular calcification due to NT5E mutations, and hypopigmentation, storage, and developmental delay due to a CLCN7 mutation.
More than 25 new disease-gene associations have been discovered. More than 1500 individuals have been evaluated by the UDP during a 5-day inpatient admission to the NIH Clinical Center, with some diagnosis made in approximately 30% most of the diagnoses are rare genetic disorders. The National Institutes of Health Undiagnosed Diseases Program (UDP) has two primary goals, to help patients who had long sought a diagnosis finally attain one, and to discover new biochemical, cellular, and physiological pathways. O-1 Diagnoses and discoveries: Insights from the NIH Undiagnosed Diseases Programġ Medical Genetics Branch, National Human Genome Research Institute
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