Detection of mosaic variants using genome sequencing in a large pediatric cohort

The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.     

A view from the clinic – Perspectives from Dutch patients and professionals on high myopia care

Purpose

To understand and compare perspectives of patients and professionals on current ophthalmologic care for high myopia, and to identify challenges and future opportunities.

Methods

Self-reported data were collected through two online questionnaires. Patient perspective was obtained from highly myopic members of a patient organisation based in the Netherlands using a 17-item questionnaire consisting of open and multiple-choice questions regarding personal experience with myopia care. The ophthalmologist perspective was obtained from practising Dutch ophthalmologists with a 12-item questionnaire of multiple-choice questions on work-related demographics, myopia care in daily practice and need for improvement. The response rate for patients was 27% (n = 136/500) and for ophthalmologists, 24% (n = 169/716).

Results

Patients were highly concerned about personal progressive loss of vision (69%) and feared their psychological well-being (82%) in case this would happen. The quality of performance of care provided by ophthalmologists was rated as excellent or satisfactory by 64% of the patients. These ratings for multidisciplinary care and insurance reimbursement were as low as 28% and 18% respectively. The mean concern among ophthalmologists about the rise in high myopia was 6.9 (SEM 0.1) on a 10-point scale. Sixty-nine per cent of the ophthalmologists reported that asymptomatic myopic patients should not be examined regularly at outpatient clinics. Ophthalmologists urged the development of clinical guidelines (74%), but did report (95%) that they informed patients about risk factors and complications. This contrasted with the view of patients, of whom 42% were discontent with information provided by ophthalmologists.

Conclusions

These questionnaires demonstrated that the current clinical care delivered to highly myopic patients is in need of improvement. The expected higher demand for myopia care in the near future requires preferred practice patterns, professionals specifically trained to manage myopic pathology, accurate and comprehensive information exchange and collaboration of in- and out-of-hospital professionals across the full eye care chain.     

Subjective versus objective sleep outcomes in older adults with and without uncoupled sleep following online cognitive behavioural therapy for insomnia

Background

Uncoupled sleep is a phenomenon characterised by a disconnect between sleep pattern and sleep complaint. This study examined the impact of uncoupled sleep on dysfunctional sleep beliefs and objective and subjective sleep outcomes in community-dwelling older adults following digitally delivered Cognitive Behavioural Therapy for Insomnia (CBT-I) to assess how these groups respond to CBT-I.

Methods

Objective sleep was measured using wrist actigraphy, subjective sleep quality via sleep diaries and the Pittsburgh Sleep Quality Index (PSQI). Dysfunctional sleep beliefs were assessed by the Dysfunctional Beliefs and Attitudes about Sleep scale (DBAS-16). All measurements were taken prior to and following a 4-week online CBT-I program. Linear mixed model and generalised linear mixed model analyses were conducted to examine objective and subjective sleep onset latency, total sleep time, wake after sleep onset and number of awakenings as well as PSQI and DBAS-16 scores, respectively.

Results

Out of 80 enrolled participants, 62 participants (55 females, 89%; 16 complaining good sleepers, 26 complaining poor sleepers, 11 non-complaining good sleepers, and nine non-complaining poor sleepers) completed the study. CBT-I reduced dysfunctional sleep beliefs across all sleeper classifications. Objective and self-reported changes in sleep parameters were demonstrated in complaining poor sleepers without uncoupled sleep. Complaining good sleepers with uncoupled sleep only reported a decrease in the number of subjective sleep awakenings. There were no changes in sleep outcomes in non-complaining good and non-complaining poor sleepers.

Conclusions

Online CBT-I was effective in improving the sleep outcomes of individuals who had both subjective and objective poor sleep. However, as the online CBT-I reduced dysfunctional sleep beliefs in all sleep groups, further examination of dysfunctional sleep beliefs and whether they mediate the outcomes of digital CBT-I in older adults will need to be conducted.     

TOPORS as a novel causal gene for Joubert syndrome

Joubert syndrome (JBTS) is a Mendelian disorder of the primary cilium defined by the clinical triad of hypotonia, developmental delay, and a distinct cerebellar malformation called the molar tooth sign. JBTS is inherited in an autosomal recessive, autosomal dominant, or X-linked recessive manner. Though over 40 genes have been identified as causal for JBTS, molecular diagnosis is not made in 30%–40% of individuals who meet clinical criteria. TOPORS encodes topoisomerase I-binding arginine/serine-rich protein, and homozygosity for a TOPORS missense variant (c.29C > A; p.(Pro10Gln)) was identified in individuals with the ciliopathy oral-facial-digital syndrome in two families of Dominican descent. Here, we report an additional proband of Dominican ancestry with JBTS found by exome sequencing to be homozygous for the identical p.(Pro10Gln) TOPORS missense variant. Query of the Mount Sinai BioMe biobank, which includes 1880 individuals of Dominican ancestry, supports a high carrier frequency of the TOPORS p.(Pro10Gln) variant in individuals of Dominican descent. Our data nominates TOPORS as a novel causal gene for JBTS and suggests that TOPORS variants should be considered in the differential of ciliopathy-spectrum disease in individuals of Dominican ancestry.     

Rates of adherence to cancer treatment guidelines in Australia and the factors associated with adherence: A systematic review

Adherence to cancer treatment clinical practice guidelines (CPGs) varies enormously across Australia, despite being associated with improved patient outcomes. This systematic review aims to characterize adherence rates to active-cancer treatment CPGs in Australia and related factors to inform future implementation strategies. Five databases were systematically searched, abstracts were screened for eligibility, a full-text review and critical appraisal of eligible studies performed, and data extracted. A narrative synthesis of factors associated with adherence was conducted, and the median adherence rates within cancer streams calculated. A total of 21,031 abstracts were identified. After duplicates were removed, abstracts screened, and full texts reviewed, 20 studies focused on adherence to active-cancer treatment CPGs were included. Overall adherence rates ranged from 29% to 100%. Receipt of guideline recommended treatments was higher for patients who were younger (diffuse large B-cell lymphoma [DLBCL], colorectal, lung, and breast cancer); female (breast and lung cancer), and male (DLBCL and colorectal cancer); never smokers (DLBCL and lung cancer); non-Indigenous Australians (cervical and lung cancer); with less advanced stage disease (colorectal, lung, and cervical cancer), without comorbidities (DLBCL, colorectal, and lung cancer); with good-excellent Eastern Cooperative Oncology Group performance status (lung cancer); living in moderately accessible places (colon cancer); and; treated in metropolitan facilities (DLBLC, breast and colon cancer). This review characterized active-cancer treatment CPG adherence rates and associated factors in Australia. Future targeted CPG implementation strategies should account for these factors, to redress unwarranted variation particularly in vulnerable populations, and improve patient outcomes (Prospero number: CRD42020222962).