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    Genetics of reticular pseudodrusen in age-related macular degeneration
    Farashi, S ; Ansell, BRE ; Wu, Z ; Abbott, CJ ; Pebay, A ; Fletcher, EL ; Guymer, RH ; Bahlo, M (CELL PRESS, 2022-04)
    Reticular pseudodrusen (RPD) are subretinal deposits and when observed with age-related macular degeneration (AMD) form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk-associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by utilising adequate imaging methods should improve our understanding of the pathophysiology of RPD.
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    A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
    Grinton, BE ; Robertson, E ; Fearnley, LG ; Scheffer, IE ; Marson, AG ; O'Brien, TJ ; Pickrell, WO ; Rees, M ; Sisodiya, SM ; Balding, DJ ; Bennett, MF ; Bahlo, M ; Berkovic, SF ; Oliver, KL (CELL PRESS, 2022-11-03)
    Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterized by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Although the variant is present in population databases (at very low frequency), there is strong clinical, genetic, and functional evidence to support pathogenicity. Recurrent variants may be due to a founder event in which the variant has been inherited from a common ancestor. Here, we report evidence of a single founder event giving rise to the SCN1B c.363C>G variant in 14 independent families with epilepsy. A common haplotype was observed in all families, and the age of the most recent common ancestor was estimated to be approximately 800 years ago. Analysis of UK Biobank whole-exome-sequencing data identified 74 individuals with the same variant. All individuals carried haplotypes matching the epilepsy-affected families, suggesting all instances of the variant derive from a single mutational event. This unusual finding of a variant causing an autosomal dominant, early-onset disease in an outbred population that has persisted over many generations can be attributed to the relatively mild phenotype in most carriers and incomplete penetrance. Founder events are well established in autosomal recessive and late-onset disorders but are rarely observed in early-onset, autosomal dominant diseases. These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important contributors to the genetic landscape than previously thought.
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    UKB.COVID19: an R package for UK Biobank COVID-19 data processing and analysis
    Wang, L ; Jackson, V ; Fearnley, L ; Bahlo, M (F1000 Research Ltd, 2022)
    COVID-19 caused by SARS-CoV-2 has resulted in a global pandemic with a rapidly developing global health and economic crisis. Variations in the disease have been observed and have been associated with the genomic sequence of either the human host or the pathogen. Worldwide scientists scrambled initially to recruit patient cohorts to try and identify risk factors. A resource that presented itself early on was the UK Biobank (UKBB), which is investigating the respective contributions of genetic predisposition and environmental exposure to the development of disease. To enable COVID-19 studies, UKBB is now receiving COVID-19 test data for their participants every two weeks. In addition, UKBB is delivering more frequent updates of death and hospital inpatient data (including critical care admissions) on the UKBB Data Portal. This frequently changing dataset requires a tool that can rapidly process and analyse up-to-date data. We developed an R package specifically for the UKBB COVID-19 data, which summarises COVID-19 test results, performs association tests between COVID-19 susceptibility/severity and potential risk factors such as age, sex, blood type, comorbidities and generates input files for genome-wide association studies (GWAS). By applying the R package to data released in April 2021, we found that age, body mass index, socioeconomic status and smoking are positively associated with COVID-19 susceptibility, severity, and mortality. Males are at a higher risk of COVID-19 infection than females. People staying in aged care homes have a higher chance of being exposed to SARS-CoV-2. By performing GWAS, we replicated the 3p21.31 genetic finding for COVID-19 susceptibility and severity. The ability to iteratively perform such analyses is highly relevant since the UKBB data is updated frequently. As a caveat, users must arrange their own access to the UKBB data to use the R package.
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    Neonatal BCG vaccination is associated with a long-term DNA methylation signature in circulating monocytes
    Bannister, S ; Kim, B ; Dominguez-Andres, J ; Kilic, G ; Ansell, BRE ; Neeland, MR ; Moorlag, SJCFM ; Matzaraki, V ; Vlahos, A ; Shepherd, R ; Germano, S ; Bahlo, M ; Messina, NL ; Saffery, R ; Netea, MG ; Curtis, N ; Novakovic, B (AMER ASSOC ADVANCEMENT SCIENCE, 2022-08-05)
    Trained immunity describes the capacity of innate immune cells to develop heterologous memory in response to certain exogenous exposures. This phenomenon mediates, at least in part, the beneficial off-target effects of the BCG vaccine. Using an in vitro model of trained immunity, we show that BCG exposure induces a persistent change in active histone modifications, DNA methylation, transcription, and adenosine-to-inosine RNA modification in human monocytes. By profiling DNA methylation of circulating monocytes from infants in the MIS BAIR clinical trial, we identify a BCG-associated DNA methylation signature that persisted more than 12 months after neonatal BCG vaccination. Genes associated with this epigenetic signature are involved in viral response pathways, consistent with the reported off-target protection against viral infections in neonates, adults, and the elderly. Our findings indicate that the off-target effects of BCG in infants are accompanied by epigenetic remodeling of circulating monocytes that lasts more than 1 year.
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    Detection of repeat expansions in large next generation DNA and RNA sequencing data without alignment
    Fearnley, LG ; Bennett, MF ; Bahlo, M (NATURE PORTFOLIO, 2022-07-30)
    Bioinformatic methods for detecting short tandem repeat expansions in short-read sequencing have identified new repeat expansions in humans, but require alignment information to identify repetitive motif enrichment at genomic locations. We present superSTR, an ultrafast method that does not require alignment. superSTR is used to process whole-genome and whole-exome sequencing data, and perform the first STR analysis of the UK Biobank, efficiently screening and identifying known and potential disease-associated STRs in the exomes of 49,953 biobank participants. We demonstrate the first bioinformatic screening of RNA sequencing data to detect repeat expansions in humans and mouse models of ataxia and dystrophy.
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    Cutting edge approaches to detecting brain mosaicism associated with common focal epilepsies: implications for diagnosis and potential therapies
    Ye, Z ; Bennett, MF ; Bahlo, M ; Scheffer, IE ; Berkovic, SF ; Perucca, P ; Hildebrand, MS (TAYLOR & FRANCIS LTD, 2021-11-02)
    INTRODUCTION: Mosaic variants arising in brain tissue are increasingly being recognized as a hidden cause of focal epilepsy. This knowledge gain has been driven by new, highly sensitive genetic technologies and genome-wide analysis of brain tissue from surgical resection or autopsy in a small proportion of patients with focal epilepsy. Recently reported novel strategies to detect mosaic variants limited to brain have exploited trace brain DNA obtained from cerebrospinal fluid liquid biopsies or stereo-electroencephalography electrodes. AREAS COVERED: The authors review the data on these innovative approaches published in PubMed before 12 June 2021, discuss the challenges associated with their application, and describe how they are likely to improve detection of mosaic variants to provide new molecular diagnoses and therapeutic targets for focal epilepsy, with potential utility in other nonmalignant neurological disorders. EXPERT OPINION: These cutting-edge approaches may reveal the hidden genetic etiology of focal epilepsies and provide guidance for precision medicine.
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    Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions
    Green, TE ; Motelow, JE ; Bennett, MF ; Ye, Z ; Bennett, CA ; Griffin, NG ; Damiano, JA ; Leventer, RJ ; Freeman, JL ; Harvey, AS ; Lockhart, PJ ; Sadleir, LG ; Boys, A ; Scheffer, IE ; Major, H ; Darbro, BW ; Bahlo, M ; Goldstein, DB ; Kerrigan, JF ; Heinzen, EL ; Berkovic, SF ; Hildebrand, MS (OXFORD UNIV PRESS, 2022-07-21)
    Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.
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    Atypical development of Broca's area in a large family with inherited stuttering
    Thompson-Lake, DGY ; Scerri, TS ; Block, S ; Turner, SJ ; Reilly, S ; Kefalianos, E ; Bonthrone, AF ; Helbig, I ; Bahlo, M ; Scheffer, IE ; Hildebrand, MS ; Liegeois, FJ ; Morgan, AT (OXFORD UNIV PRESS, 2022-04-29)
    Developmental stuttering is a condition of speech dysfluency, characterized by pauses, blocks, prolongations and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene-brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering. We studied a four-generation family, 16 family members were included in genotyping analysis. T1-weighted and diffusion-weighted MRI scans were conducted on seven family members (six male; aged 9-63 years) with two age and sex matched controls without stuttering (n = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography. We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca's area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of P < 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left P = 0.017; right P = 0.037), and a larger right globus pallidus was associated with more severe stuttering (rho = 0.86, P = 0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype. Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca's area and the striatum underpinning stuttering in these individuals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering.
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    Self-reported impact of developmental stuttering across the lifespan
    Boyce, JO ; Jackson, VE ; van Reyk, O ; Parker, R ; Vogel, AP ; Eising, E ; Horton, SE ; Gillespie, NA ; Scheffer, IE ; Amor, DJ ; Hildebrand, MS ; Fisher, SE ; Martin, NG ; Reilly, S ; Bahlo, M ; Morgan, AT (WILEY, 2022-10)
    AIM: To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. METHOD: Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. RESULTS: A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18-93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7-17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). INTERPRETATION: The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies. WHAT THIS PAPER ADDS: Half of the study cohort had a family history of stuttering. While 75.9% of participants had sought stuttering therapy, only 15.5% identified as having recovered. There was a significant negative correlation between age and stuttering frequency and severity in adults.
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    Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome
    Stephenson, SEM ; Costain, G ; Blok, LER ; Silk, MA ; Nguyen, TB ; Dong, X ; Alhuzaimi, DE ; Dowling, JJ ; Walker, S ; Amburgey, K ; Hayeems, RZ ; Rodan, LH ; Schwartz, MA ; Picker, J ; Lynch, SA ; Gupta, A ; Rasmussen, KJ ; Schimmenti, LA ; Klee, EW ; Niu, Z ; Agre, KE ; Chilton, I ; Chung, WK ; Revah-Politi, A ; Au, PYB ; Griffith, C ; Racobaldo, M ; Raas-Rothschild, A ; Ben Zeev, B ; Barel, O ; Moutton, S ; Morice-Picard, F ; Carmignac, V ; Cornaton, J ; Marle, N ; Devinsky, O ; Stimach, C ; Wechsler, SB ; Hainline, BE ; Sapp, K ; Willems, M ; Bruel, A ; Dias, K-R ; Evans, C-A ; Roscioli, T ; Sachdev, R ; Temple, SEL ; Zhu, Y ; Baker, JJ ; Scheffer, IE ; Gardiner, FJ ; Schneider, AL ; Muir, AM ; Mefford, HC ; Crunk, A ; Heise, EM ; Millan, F ; Monaghan, KG ; Person, R ; Rhodes, L ; Richards, S ; Wentzensen, IM ; Cogne, B ; Isidor, B ; Nizon, M ; Vincent, M ; Besnard, T ; Piton, A ; Marcelis, C ; Kato, K ; Koyama, N ; Ogi, T ; Goh, ES-Y ; Richmond, C ; Amor, DJ ; Boyce, JO ; Morgan, AT ; Hildebrand, MS ; Kaspi, A ; Bahlo, M ; Fridriksdottir, R ; Katrinardottir, H ; Sulem, P ; Stefansson, K ; Bjornsson, HT ; Mandelstam, S ; Morleo, M ; Mariani, M ; Scala, M ; Accogli, A ; Torella, A ; Capra, V ; Wallis, M ; Jansen, S ; Waisfisz, Q ; de Haan, H ; Sadedin, S ; Lim, SC ; White, SM ; Ascher, DB ; Schenck, A ; Lockhart, PJ ; Christodoulou, J ; Tan, TY (CELL PRESS, 2022-04-07)
    Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.