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Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)(>300) and a further nine individuals with (GAA)(>250). PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)(>300) and only 2/311 control individuals (0.6%) had a pure (GAA)(>250). In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)(>335) and a further six had (GAA)(>250), whereas 10/190 (5.3%) control subjects had (GAA)(>250) but none were (GAA)(>335). The combined data suggest (GAA)(>335) are disease causing and fully penetrant (p = 6.0 × 10(−8), OR = 72 [95% CI = 4.3–1,227]), while (GAA)(>250) is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R(2) = 0.44, p = 0.00045, slope = −0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.

AmpSeqR test dataset extracted from BioProject PRJNA381546 andhttps://github.com/lerch-a/HaplotypR &nbsp

Conversion of adenosine to inosine in RNA by ADAR enzymes occurs at thousands of sites in the human transcriptome, and is essential for healthy brain development. This process, known as ‘RNA editing’, is dysregulated in many neuropsychiatric diseases, but is little understood at the level of individual neurons. We examined full-length nuclear transcriptomes of 3,055 neurons from six cortical regions of a neurotypical post-mortem female donor and identified 40,861 high-confidence edited sites. The majority of sites were located within Alu repeats in introns or 3’ UTRs, and were present in previously published RNA editing databases. We identified 15,784 putative novel RNA editing sites, 30% of which were also detectable in independently generated neuronal transcriptomes from unrelated donors. The strongest correlates of global editing rates were expression levels of small nucleolar RNAs from the SNORD115 and SNORD116 cluster (15q11), known to modulate serotonin receptor processing and to colocalize with ADAR2, one of three known RNA editing enzymes in humans. As expected, expression of DNA and RNA binding proteins were negatively associated with editing. We present evidence for dysregulated RNA editing in six rare genetic conditions; and report 117 differentially edited sites between cortical regions and neuronal subtypes. These results provide spatial and neurophenotypic context for 1,871 and 998 sites that are differentially edited in the brains of schizophrenic and autistic patients respectively, and a reference for future studies of RNA editing in single brain cells from these cohorts.

Background: The evolution of tuberculosis (TB) disease during the clinical latency period remains incompletely understood., Methods: 250 HIV-uninfected, adult household contacts of rifampicin-resistant TB with a negative symptom screen underwent baseline 18 F-Fluorodeoxyglucose positron emission and computed tomography (PET/CT), repeated in 112 after 5-15 months. Following South African and WHO guidelines, participants did not receive preventive therapy. All participants had intensive baseline screening with spontaneous, followed by induced, sputum sampling and were then observed for an average of 4.7 years for culture-positive disease. Baseline PET/CT abnormalities were evaluated in relation to culture-positive disease., Results: At baseline, 59 (23.6%) participants had lung PET/CT findings consistent with TB of which 29 (11.6%) were defined as Subclinical TB, and 30 (12%) Subclinical TB-inactive. A further 83 (33.2%) had other lung parenchymal abnormalities and 108 (43.2%) had normal lungs. Over 1107-person years of follow-up 14 cases of culture-positive TB were diagnosed. Six cases were detected by intensive baseline screening, all would have been missed by the South African symptom-based screening strategy and only one detected by a WHO-recommended chest X-Ray screening strategy. Those with baseline Subclinical TB lesions on PET/CT were significantly more likely to be diagnosed with culture-positive TB over the study period, compared to those with normal lung parenchyma (10/29 [34.5%] vs 2/108 [1.9%], Hazard Ratio 22.37 [4.89-102.47, p<0.001])., Conclusions: These findings challenge the latent/active TB paradigm demonstrating that subclinical disease exists up to 4 years prior to microbiological detection and/or symptom onset. There are important implications for screening and management of TB.