====== 100,000 Genomes Project  ======

The 100,000 Genomes Project is a UK Government project that is sequencing whole genomes from National Health Service patients. The project is focusing on rare diseases, some common types of cancer, and infectious diseases.
----
NOTCH2NLC is 1 of 3 nearly identical, functional human [[NOTCH2]] (600275)-like genes on [[chromosome 1]]q21.1 The NOTCH2L proteins appear to regulate [[Notch signaling pathway]] and promote cortical [[neurogenesis]].
----
The objective of Yau et al. in a [[study]] was to determine the [[prevalence]] of the [[GGC]]-repeat expansion in [[NOTCH2NLC]] in whites presenting with [[movement disorder]]s.

They searched for the GGC-repeat expansion in NOTCH2NLC using repeat-primed [[polymerase chain reaction]] in 203 patients with [[essential tremor]], 825 patients with PD, 194 patients with spinocerebellar ataxia, 207 patients with "possible" or "probable" MSA, and 336 patients with pathologically confirmed MSA. They also screened 30,008 patients enrolled in the [[100,000 Genomes Project]] for the same mutation using ExpansionHunter, followed by a repeat-primed polymerase chain reaction. All possible expansions were confirmed by Southern blotting and/or long-read sequencing.

They identified 1 patient who carried the NOTCH2NLC mutation in the essential tremor cohort, and 1 patient presenting with recurrent encephalopathy and postural tremor/parkinsonism in the 100,000 Genomes Project.

GGC-repeat expansion in NOTCH2NLC is rare in whites presenting with movement disorders. In addition, existing whole-genome sequencing data are useful in case ascertainment
((Yau WY, Vandrovcova J, Sullivan R, Chen Z, Zecchinelli A, Cilia R, Stefano D, Murray M, Carmona S; Genomics England Research Consortium, Chelban V, Ishiura H, Tsuji S, Jaunmuktane Z, Turner C, Wood NW, Houlden H. Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients With Movement Disorders. Mov Disord. 2020 Oct 7. doi: 10.1002/mds.28302. Epub ahead of print. PMID: 33026126.)).
----
Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico-based screening using whole-genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases
((Chen Z, Yan Yau W, Jaunmuktane Z, Tucci A, Sivakumar P, Gagliano Taliun SA, Turner C, Efthymiou S, Ibáñez K, Sullivan R, Bibi F, Athanasiou-Fragkouli A, Bourinaris T, Zhang D, Revesz T, Lashley T, DeTure M, Dickson DW, Josephs KA, Gelpi E, Kovacs GG, Halliday G, Rowe DB, Blair I, Tienari PJ, Suomalainen A, Fox NC, Wood NW, Lees AJ, Haltia MJ; Genomics England Research Consortium, Hardy J, Ryten M, Vandrovcova J, Houlden H. Neuronal intranuclear inclusion disease is genetically heterogeneous. Ann Clin Transl Neurol. 2020 Aug 10;7(9):1716–25. doi: 10.1002/acn3.51151. Epub ahead of print. PMID: 32777174; PMCID: PMC7480908.)).