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BackgroundBirt–Hogg–Dubé (BHD) syndrome is an autosomal dominant multisystem disorder with skin (fibrofolliculomas or trichodiscomas), lung (cysts and pneumothorax) and kidney (renal cell carcinoma) tumours. Although colorectal neoplasia was reported initially to be part of the BHD phenotype, some recent studies have not confirmed this association.MethodsA series of clinical and laboratory studies was undertaken to investigate possible relationships between colorectal neoplasia and the BHD gene (FLCN). The studies investigated whether individuals with familial colorectal cancer of unknown cause might have unsuspected germline FLCN mutations, looked for somatic FLCN C8 tract mutations in microsatellite unstable sporadic colorectal cancers, and assessed the risk of colorectal neoplasia and possible genotype–phenotype correlations in BHD patients.ResultsAlthough it was found previously that germline FLCN mutations can be detected in ∼5% of patients with familial renal cell carcinoma, germline FLCN mutations were not detected in 50 patients with familial non-syndromic colorectal cancer. Analysis of genotype-phenotype correlations for two recurrent FLCN mutations identified in a subset of 51 families with BHD demonstrated a significantly higher risk of colorectal neoplasia in c.1285dupC mutation (within the exon 11 C8 mononucleotide tract) carriers than in c.610delGCinsTA mutation carriers (χ2=5.78, p=0.016). Somatic frameshift mutations in the FLCN exon 11 C8 mononucleotide tract were detected in 23% of sporadic colorectal cancers with microsatellite instability, suggesting that FLCN inactivation might contribute to colorectal tumourigenesis.ConclusionsThese findings suggest that the previously reported clinical heterogeneity for colorectal neoplasia may reflect allelic heterogeneity and the risk of colorectal neoplasia in BHD syndrome requires further investigation.

BackgroundSilver-Russell syndrome (SRS) is an imprinting disorder characterised by prenatal and postnatal growth restriction, but its clinical features are non-specific and its differential diagnosis is broad. Known molecular causes of SRS include imprinting disturbance, single nucleotide variant (SNV), CNV or UPD affecting several genes; however, up to 40% of individuals with a clinical diagnosis of SRS currently receive no positive molecular diagnosis.MethodsTo determine whether whole-genome sequencing (WGS) could uncover pathogenic variants missed by current molecular testing, we analysed data of 72 participants recruited to the 100,000 Genomes Project within the clinical category of SRS.ResultsIn 20 participants (27% of the cohort) we identified genetic variants plausibly accounting for SRS. Coding SNVs were identified in genes including CDKN1C, IGF2, IGF1R and ORC1. Maternal-effect variants were found in mothers of five participants, including two participants with imprinting disturbance and one with multilocus imprinting disorder. Two regions of homozygosity were suggestive of UPD involving imprinted regions implicated in SRS and Temple syndrome, and three plausibly pathogenic CNVs were found, including a paternal deletion of PLAGL1. In 48 participants with no plausible pathogenic variant, unbiased analysis of SNVs detected a potential association with STX4.ConclusionWGS analysis can detect UPD, CNV and SNV and is potentially a valuable addition to diagnosis of SRS and related growth-restricting disorders.

Abstract Objective Chronic pain is a prevalent and disabling condition. Reboot Online was developed as a multidisciplinary and widely accessible online treatment program for chronic pain. It has been shown to be effective in clinical trials, but the effectiveness of this program in routine care settings remains unknown. This study aimed to examine program adherence and effectiveness in a real-world sample of participants completing Reboot Online in the community. Design and subjects A retrospective cohort study was conducted using real-world data from participants referred the Reboot Online program by clinicians as part of their routine care, from April 2017 to April 2019. Methods Routinely collected data on program adherence, participant demography and clinical outcomes were included in the analyses. Measures included the Pain Self Efficacy Questionnaire, Brief Pain Inventory, Tampa Scale of Kinesiophobia, Pain-Disability Index, and Patient Health Questionnaire 9-item (depression). Logistic regression was used to investigate whether certain factors predict program adherence (completion versus noncompletion), and linear mixed models were used to examine effectiveness. Results In total, 867 participants were included in the analyses, and 583 engaged with at least one Reboot Online lesson. Of these, 42% (n = 247) completed the course in its entirety, with rurality and lower Tampa scores being significant predictors of adherence. Completers demonstrated significant improvements across all outcome measures (effect sizes ranging from 0.22 to 0.51). Conclusions Reboot Online is an effective treatment for chronic pain in the routine care setting. Adherence was variable (overall 42%), and could be predicted by rurality and less fear of movement at baseline.

Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia (‘Lenz’-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome (‘Lenz’) usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.

BackgroundIdentification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results.MethodsWe investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility.ResultsIn the pilot cohort, 31/3366 (0.92%) individuals had a CNV involving one or more of 16/39 CPGs. 30/31 CNVs involved a tumour suppressor gene (TSG), and 1/30 a proto-oncogene (gain of MET). BMPR1A, TSC2 and TMEM127 were affected in multiple cases. In the second stage analysis, 49/10 454 (0.47%) individuals in the extended cohort had 50 CNVs involving 24/105 CPGs. 43/50 CNVs involved a TSG and 7/50 a proto-oncogene (4 gains, 3 deletions). The most frequently involved genes, FLCN (n=10) and SDHA (n=7), map to the Smith-Magenis and cri-du-chat regions, respectively.ConclusionIncidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance.

Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans.

Purpose The aim of this study was to examine the association between selective serotonin reuptake inhibitor (SSRI) therapy and rehabilitation outcomes, specifically disability and quality of life (QOL), in a real-world setting of multi-ethnic Asian patients with first-ever stroke. Methods In this prospective observational pilot cohort study, we included patients with first-ever stroke admitted to two inpatient rehabilitation centres in Singapore between January and July 2018. Outcomes were measured using Functional Independence Measure (FIM)-motor scale, modified Barthel Index (MBI) and the Stroke and Aphasia Quality of Life Scale-39 generic (SAQOL-39g) questionnaire. Linear regression was used to assess the association between SSRI therapy and outcomes. Regression coefficients and 95% confidence intervals (CIs) were reported. Results Among 57 patients included for analyses, 38.6% received SSRIs. Although SSRI therapy was significantly associated with gains in MBI (coefficient 11.35; 95% CI 0.21–22.50) and SAQOL-39g overall score (coefficient 0.45; 95% CI 0.05–0.85) based on simple linear regression, no significant association between SSRI therapy and any of the investigated outcomes was found after adjustment for confounders. However, an increase in the mean number of physiotherapy and occupational therapy (PT/OT) sessions per day significantly improved FIM-motor (coefficient 16.86; 95% CI 2.64–31.07) and MBI (coefficient 22.79; 95% CI 2.35–43.23) scores. Conclusion SSRI therapy did not improve disability and QOL in multi-ethnic Asian patients with first-ever stroke undergoing rehabilitation.

Human imprinting disorders can provide critical insights into the role of imprinted genes in human development and health, and the molecular mechanisms that regulate genomic imprinting. To illustrate these concepts we review the clinical and molecular features of several human imprinting syndromes including Beckwith-–Wiedemann syndrome, Silver-–Russell syndrome, Angelman syndrome, Prader-–Willi syndrome, pseudohypoparathyroidism, transient neonatal diabetes, familial complete hydatidiform moles and chromosome 14q32 imprinting domain disorders.

BackgroundChronic pruritus of unknown origin (CPUO) is poorly understood and lacks effective treatment options.ObjectivesWe aimed to elucidate abnormalities in the sweat apparatus of patients with CPUO, and to assess efficacy and safety of treatment with systemic retinoids.MethodsAn initial case–control study included 20 affected patients and five healthy controls, for whom heat and sweating were induced, either through a standardized exercise protocol or ingestion of hot water. In vivo high-definition optical coherence tomography, whole-body starch-iodine testing, and skin biopsy for immunofluorescence staining were done to evaluate for sweat duct obstruction. A subsequent retrospective cohort analysis included 56 patients with CPUO, seen at an Itch subspecialty clinic of a single tertiary referral centre, who failed conventional treatments and were treated with isotretinoin and/or acitretin from May 2014 to November 2020. Treatment response to retinoids was defined as a sustained reduction in itch score of ≥2/10. Safety was assessed by proportion stopping treatment due to side effects.ResultsIn vivo imaging in 19 (95%) patients revealed features of partial keratinaceous sweat duct obstruction with statistically significant luminal dilatation compared to controls. Immunofluorescence studies of three patients’ paired lesional/non-lesional biopsies revealed dermcidin accumulation within sweat glands coupled with dermcidin leakage in itchy skin. Fifty-six patients (mean [SD] age 55.2 [17.5] years, 69.6% male) were treated with systemic retinoids. Mean (SD) duration of itch was 116.3 (140.4) months and mean (SD) itch score was 8.2 (1.8). Forty-one (73.2%) initially received isotretinoin, and 15 (26.8%) acitretin. At three months, mean itch score reduced by 2.38 (95% CI -3.2 to −1.6, p  < 0.0001). Thirty-eight (67.9%) had a sustained response. Eight (14.81%) achieved an itch score of 0 or 1, with four stopping treatment for a mean (SD) of 318.5 (291.2) days without relapse. Eight (14.3%) stopped or switched retinoid due to adverse effects, with similar incidences between both retinoids, the commonest being dryness.ConclusionBased on novel findings from physiological imaging studies identifying partial keratinaceous sweat duct obstruction in CPUO, we instituted systemic retinoid treatment to address the underlying pathology. In patients who failed conventional therapies, the treatment appears effective and safe.

De novo mutations in protein-coding genes are a well-established cause of developmental disorders 1 . However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations 1 , 2 . Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders. By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.