Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases.

BACKGROUND: Diagnostic use of gene panel next-generation sequencing (NGS) techniques is commonplace for individuals with inherited retinal dystrophies (IRDs), a highly genetically heterogeneous group of disorders. However, these techniques have often failed to capture the complete spectrum of genomic variation causing IRD, including CNVs. This study assessed the applicability of introducing CNV surveillance into first-tier diagnostic gene panel NGS services for IRD. METHODS: Three read-depth algorithms were applied to gene panel NGS data sets for 550 referred individuals, and informatics strategies used for quality assurance and CNV filtering. CNV events were confirmed and reported to referring clinicians through an accredited diagnostic laboratory. RESULTS: We confirmed the presence of 33 deletions and 11 duplications, determining these findings to contribute to the confirmed or provisional molecular diagnosis of IRD for 25 individuals. We show that at least 7% of individuals referred for diagnostic testing for IRD have a CNV within genes relevant to their clinical diagnosis, and determined a positive predictive value of 79% for the employed CNV filtering techniques. CONCLUSION: Incorporation of CNV analysis increases diagnostic yield of gene panel NGS diagnostic tests for IRD, increases clarity in diagnostic reporting and expands the spectrum of known disease-causing mutations

A clinical and molecular characterisation of CRB1-associated maculopathy

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype–phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull’s-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes—intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date

The acute effects of aerobic exercise on sleep in patients with unipolar depression: a randomized controlled trial

Study Objectives Insomnia increases the risk of negative disease trajectory, relapse, and suicide in patients with depression. We aimed at investigating the effects of a single bout of aerobic exercise, performed after 02:00 pm, on the subsequent night’s sleep in patients with depression. Methods The study was designed as a two-arm parallel-group, randomized, outcome assessor-blinded, controlled, superiority trial. Patients between 18 and 65 years of age with a primary diagnosis of unipolar depression were included. The intervention was a single 30-minute bout of moderate aerobic exercise. The control group sat and read for 30 minutes. The primary outcome was sleep efficiency measured by polysomnography. Secondary outcomes were other polysomnographic variables, subjective sleep quality, daytime sleepiness, mood states, and adverse events. Results Ninety-two patients were randomized to the exercise (N = 46) or control group (N = 46). There were no clinically relevant differences at baseline. Intent-to-treat analysis ANCOVA of follow-up sleep efficiency, adjusted for baseline levels and minimization factors, did not detect a significant effect of the allocation (β = −0.93, p = 0.59). There was no evidence for significant differences between both groups in any other objective or subjective sleep outcomes, daytime sleepiness, or adverse events. The intervention had an immediate positive effect on mood states, including depressiveness (β = −0.40, p = 0.003). Conclusions This is the first trial to study the effects of a single bout of aerobic exercise on sleep in patients with depression to the best of our knowledge. Aerobic exercise had no effect on sleep efficiency but had a strong beneficial effect on mood and did not increase adverse outcomes. These results add to the growing body of evidence that, contrary to sleep hygiene recommendations, exercise after 02:00 pm is not detrimental for sleep. Clinical Trial Registration Clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/NCT03673397. Protocol registered on September 17, 2018

PHYH c.678+5G>T Leads to In-Frame Exon Skipping and Is Associated With Attenuated Refsum Disease

PURPOSE: To investigate the molecular effect of the variant PHYH:c.678+5G>T. This variant has conflicting interpretations in the ClinVar database and a maximum allele frequency of 0.0045 in the South Asian population in gnomAD. METHODS: We recruited patients from Moorfields Eye Hospital (London, UK) and Buenos Aires, Argentina, who were diagnosed with retinitis pigmentosa and found to have biallelic variants in PHYH, with at least one being c.678+5G>T. Total RNA was purified from PaxGene RNA-stabilized whole-blood samples, followed by reverse transcription to cDNA, PCR amplification of the canonical PHYH transcript, Oxford Nanopore Technologies library preparation, and single-molecule amplicon sequencing. RESULTS: Four patients provided a blood sample. One patient had isolated retinitis pigmentosa and three had mild extraocular findings. Blood phytanic acid levels were normal in two patients, mildly elevated in one, and markedly high in the fourth. Retinal evaluation showed an intact ellipsoid zone as well as preserved autofluorescence in the macular region in three of the four patients. In all patients, we observed in-frame skipping of exons 5 and 6 in 31.1% to 88.4% of the amplicons and a smaller proportion (0% to 11.3% of amplicons) skipping exon 6 only. CONCLUSIONS: We demonstrate a significant effect of PHYH:c.678+5G>T on splicing of the canonical transcript. The in-frame nature of this may be in keeping with a mild presentation and higher prevalence in the general population. These data support the classification of the variant as pathogenic, and patients harboring a biallelic genotype should undergo phytanic acid testing

The effects of exercise on sleep in unipolar depression: A systematic review and network meta-analysis

Insomnia predicts the onset, course, and reoccurrence of unipolar depression. However, systematic reviews of treatment options for insomnia in unipolar depression are lacking. After screening 7725 records, 17 trials comprising 1645 patients randomized to 13 treatments were included for quantitative synthesis. Network meta-analysis showed that compared to a passive control condition, all exercise interventions except moderate aerobic exercise alone resulted in significantly better sleep outcomes. Compared with treatment as usual, mind-body exercise plus treatment as usual (SMD: −0.46; 95% CI: −0.80, −0.12) and vigorous strength exercise (SMD: −0.61; 95% CI: −1.12, −0.10) were significantly more effective. Pairwise meta-analyses showed that mind-body exercise (SMD: −0.54; 95% CI: −0.85, −0.23) had beneficial effects compared to passive control. The network meta-analysis is statistically very robust with low heterogeneity, incoherence, and indirectness. However, confidence in the findings was moderate to very low, primarily due to within-study bias. This is the first network meta-analysis to assess exercise's efficacy to improve sleep quality in patients with depression. The findings confirm the benefits of exercise as an add-on treatment for depression. This consolidation of the current state of evidence can help clinicians make evidence-based decisions

Wirkmechanismen körperlicher Aktivität auf den Schlaf bei Patienten mit Depression: Ein Narratives Review

Insomnie ist eines der Kardinalsymptome einer unipolaren Depression. Insomnie hat dabei einen negativen Einfluss auf den Krankheitsverlauf, ist eines der häufigsten Residualsymptome und ein Risikofaktor für ein Rezidiv. Im vorliegenden Überblick werden mögliche Wirkmechanismen von körperlichem Training auf den Schlaf bei Patienten mit Depression zusammengefasst. Die vorgestellten Mechanismen beruhen auf Daten aus In-vitro‑, Tier- und Humanstudien, welche die Effekte von Kraft‑, Ausdauer- und Mind-Body-Training untersuchen. Sowohl akutes Training als auch über mehrere Wochen regelmäßig absolviertes Training kann über verschiedene Signalwege positive Effekte auf den Schlaf bei Patienten mit Depression haben. Folgende Mechanismen sind dabei relevant: Zeitgebereffekte, Energiekonservierung, Regeration, Thermoregulation, psychophysiologische Effekte und „tissue–brain crosstalk“. Diese Befunde sind relevant, um die Therapie von nichtorganischen Schlafstörungen im Rahmen einer depressiven Episode besser zu verstehen, weiterzuentwickeln und auf individuelle Patienten anzupassen

Clinical, Genetic, Imaging and Electrophysiological Findings in a Cohort of Patients With GUCA1A-Associated Retinopathy

PURPOSE: To report findings in GUCA1A-associated retinopathy, a rare autosomal-dominant retinopathy. METHODS: Clinical features and investigations from molecularly confirmed patients at a large referral center were analyzed (retrospective cohort study). RESULTS: Nineteen patients (14 families), with five different variants, were included: p.(Tyr99Cys) in 10 families and p.(Leu84Phe), p.(Ile107Thr), p.(Glu111Ala), and p.(leu176Phe) in 1 family each. Mean (SD) ages at first and last visits were 38 (17) and 48 (15) years, respectively. Mean (SD) logMAR visual acuities at the first and last visits were 0.67 (0.61) and 0.94 (0.58) for right eyes and 0.63 (0.63) and 0.95 (0.74) for left eyes. Acuities ranged from 0.00 logMAR to no light perception. Most described progressive problems with central and color vision. Across 144 patient visits, logMAR acuity correlated with age (Spearman coefficients of 0.43 and 0.54 for right and left eyes, P < 0.001), with a high interocular correlation (coefficient 0.90, P < 0.001). Optical coherence tomography showed irregularity and then loss of the central ellipsoid zone. Ultra-widefield imaging showed peripheral degeneration in some patients. Electrophysiology (n = 13) was consistent with cone dystrophy (n = 11) or macular dystrophy (n = 2). Compared with the common p.(Tyr99Cys) variant, patients with p.(Glu111Ala) (n = 2) had worse vision; those with p.(Leu84Phe) (n = 3) were younger with earlier-onset visual loss. Patients with p.(Ile107Thr) (n = 2) showed later presentation, with milder acuity reduction. CONCLUSIONS: We present genotypic and phenotypic findings from the largest cohort with GUCA1A retinopathy. Most had progressive visual loss and electrophysiologic evidence of cone dystrophy. Possible genotype-phenotype correlations emerged, but subgroups were small for four of five variants