New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies

Abstract

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype–phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.

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The inspired sinewave technique: A novel method to measure lung volume and ventilatory heterogeneity

Abstract

The Inspired Sinewave Technique (IST) is a novel method which can provide simple, non-invasive cardiopulmonary measurements. Over successive tidal-breaths the concentration of a tracer gas (i.e. nitrous oxide, N₂O) is sinusoidally modulated in inspired air. Using a single-compartment tidal-ventilation lung model, the resulting amplitude/phase of the expired sinewave allows estimation of end-expired lung volume (ELV), pulmonary blood flow and three indices for ventilatory heterogeneity (VH; ELV₁₈₀/FRC_pleth, ELV₁₈₀/FRC_pred and ELV₆₀/ELV₁₈₀).

This investigation aimed to determine: the repeatability and agreement of ELV with FRC_pleth, and, as normal ageing results in well-established changes in pulmonary structure and function, whether the IST estimates of ELV and VH are age dependent.

48 healthy never-smoker participants (20–86 years) underwent traditional pulmonary function testing: (e.g. spirometry, body plethysmography) and the IST test which consisted of 4 minutes of quiet breathing through a facemask while inspired N₂O concentrations are oscillated in a sinewave pattern with a fixed mean (4%) and amplitude (3%) and a period of either 180 seconds or 60 seconds.

ELV₁₈₀/FRC_pleth and ELV₁₈₀/FRC_pred were age dependent (average decreases of 0.58% and 0.48% per year) suggesting an increase in VH with advancing age. ELV showed a mean bias of −1.09L vs. FRC_pleth, but when normalised for the effects of age this bias reduced to −0.35L. The IST test has potential to provide clinically useful information necessitating further study (e.g. for mechanically ventilated or obstructive lung disease patients), but these findings suggest that the increases in VH with healthy ageing must be accounted for in clinical investigations.

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Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein–Taybi syndrome

In 2016, we described that missense variants in parts of exons 30 and 31 of CREBBP can cause a phenotype that differs from Rubinstein–Taybi syndrome (RSTS). Here we report on another 11 patients with variants in this region of CREBBP (between bp 5,128 and 5,614) and two with variants in the homologous region of EP300. None of the patients show characteristics typical for RSTS. The variants were detected by exome sequencing using a panel for intellectual disability in all but one individual, in whom Sanger sequencing was performed upon clinical recognition of the entity. The main characteristics of the patients are developmental delay (90%), autistic behavior (65%), short stature (42%), and microcephaly (43%). Medical problems include feeding problems (75%), vision (50%), and hearing (54%) impairments, recurrent upper airway infections (42%), and epilepsy (21%). Major malformations are less common except for cryptorchidism (46% of males), and cerebral anomalies (70%). Individuals with variants between bp 5,595 and 5,614 of CREBBP show a specific phenotype (ptosis, telecanthi, short and upslanted palpebral fissures, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum). 3D face shape demonstrated resemblance to individuals with a duplication of 16p13.3 (the region that includes CREBBP), possibly indicating a gain of function. The other affected individuals show a less specific phenotype. We conclude that there is now more firm evidence that variants in these specific regions of CREBBP and EP300 result in a phenotype that differs from RSTS, and that this phenotype may be heterogeneous.

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Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features

Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in OMIM genes and non-OMIM genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients, in order to identity novel MH-ID genes.

Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes PSD-95, a protein expressed in various tissues including the brain. In neurons, PSD-95 is localized at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one for a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients showed mild-to-moderate ID, similar marfanoid features, including a long face, high arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus).

Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.

Sixty-four probands presenting with at least intellectual disability with marfanoid habitus were analyzed by whole exome sequencing, 33 in a trio and 31 in a solo strategy in order to provide appropriate management, genetic counseling and to study diagnosis yield in this phenotype. After analyzing the data using classical approaches allowing to reach a molecular diagnosis in 53.2% of cases, a bioinformatic filtration procedure was applied on the cohort, consisting of searching for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. This strategy allowed to highlight DLG4 as a novel disease-causing gene responsible for intellectual disability and probably marfanoid features. mRNA studies on the blood of the 3 patients showed decreased gene expression in two patients and aberrant splicing leading to a premature stop codon in one patient confirming the likely pathogenic effect of the variants. DLG4 gene represent a good candidate gene as its PSD-95 protein product is localized at the post-synaptic density, is associated with glutamatergic receptor signaling and participates in dendritogenesis. Several mouse models support the pathogenicity of DLG4 expression deficiency.

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Early exercise for lifelong benefit: sustained cardiac programming in rats and the potential translation to humans

Abstract

It is well established that the intrauterine environment has the potential to determine the lifelong health of an organism. For example, prenatal stress can reduce gestational length and have negative downstream effects on endocrine and metabolic outcomes, which propagate across subsequent generations.

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Stimulus dependent neural oscillatory patterns show reliable statistical identification of Autism Spectrum Disorder in a face perceptual decision task

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and communication as well as by repetitive and restrictive behaviors and interests (American Psychiatric Association, 2013). Given the heterogeneity of this spectrum (Walsh et al., 2011) it is of paramount importance to identify experimental paradigms that are able to target cognitive processes that can be translated into the development of disease related biomarkers. Impaired attentional allocation to social features (including joint attention) (Amaral et al., 2015) or face processing deficits (Tavares et al., 2016) include the type of cognitive processes that might be targeted.

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Occurrence of Thalamic High Frequency Oscillations in Patients with Different Tremor Syndromes

Abnormal oscillatory activity in the basal ganglia plays a pivotal role in the pathophysiology of movement disorders. In particular, an increase of beta activity (15-30Hz) in the subthalamic nucleus (STN) has been suggested to underlie slowing of movement in Parkinson's disease (PD) (Kühn et al., 2009; Ray et al., 2008). Beta oscillations are modulated by dopaminergic medication (Brown et al., 2001; Levy et al., 2002; Priori et al., 2004) and voluntary movement (Cassidy et al., 2002; Levy et al., 2002).

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Creatine kinase level and its relationship with quantitative electromyographic characteristics in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that involves both upper and lower motor neurons and eventually leads to muscle weakness, muscle atrophy, bulbar palsy, and respiratory failure. Creatine kinase (CK) is an enzyme that catalyzes the reversible conversion of creatine and utilizes adenosine triphosphate (ATP) to generate phosphocreatine and adenosine diphosphate. This enzyme is important in tissues and cells that rapidly consume ATP, particularly skeletal muscle.

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Long-term neurophysiological and clinical response in patients with chronic inflammatory demyelinating polyradiculoneuropathy treated with subcutaneous immunoglobulin

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated disorder presenting with sub-acute onset and progressive symmetrical weakness over at least 2 months, involving proximal and distal limb muscles, associated with hypo/areflexia and impaired sensory functions (Latov, 2014; Koller et al., 2005).

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Listening in the bog: II. Neural correlates for acoustic interactions and spacing between Sphagniana sphagnorum males

Abstract

Males of the katydid Sphagniana sphagnorum maintain inter-male distances from one another using agonistic song interactions with a frequency-modulated song that consists of alternating audio and ultrasonic parts. We studied the neuronal representation of this song in auditory receptors and interneurons of receivers, using playbacks of songs that mimicked the absolute and relative sound pressure levels of the two song modes varying with distance. The tuning and sensitivity of both receptors and interneurons strongly determine their responses to the two song modes at different distances. Low-frequency interneurons respond preferentially to the audio mode of the song at larger distances. High-frequency (HF) interneurons respond preferentially to the HF component of the song at close range. 'Switch interneurons' are sensitive to both spectral song components, but exhibit a typical activity switch towards the high-frequency mode at distances nearer than 3–6 m. The activity of the latter two groups of interneurons correlates with the distance in the field at which males begin to interact acoustically with their neighbours. Important information about the rate of changes in the song mode is represented by the afferent activity despite the influence of the masking song produced by a sympatric katydid species.

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Inferring causal relationships between phenotypes using summary statistics from genome-wide association studies

Abstract

Genome-wide association studies (GWAS) have successfully identified numerous genetic variants associated with diverse complex phenotypes and diseases, and provided tremendous opportunities for further analyses using summary association statistics. Recently, Pickrell et al. developed a robust method for causal inference using independent putative causal SNPs. However, this method may fail to infer the causal relationship between two phenotypes when only a limited number of independent putative causal SNPs identified. Here, we extended Pickrell's method to make it more applicable for the general situations. We extended the causal inference method by replacing the putative causal SNPs with the lead SNPs (the set of the most significant SNPs in each independent locus) and tested the performance of our extended method using both simulation and empirical data. Simulations suggested that when the same number of genetic variants is used, our extended method had similar distribution of test statistic under the null model as well as comparable power under the causal model compared with the original method by Pickrell et al. But in practice, our extended method would generally be more powerful because the number of independent lead SNPs was often larger than the number of independent putative causal SNPs. And including more SNPs, on the other hand, would not cause more false positives. By applying our extended method to summary statistics from GWAS for blood metabolites and femoral neck bone mineral density (FN-BMD), we successfully identified ten blood metabolites that may causally influence FN-BMD. We extended a causal inference method for inferring putative causal relationship between two phenotypes using summary statistics from GWAS, and identified a number of potential causal metabolites for FN-BMD, which may provide novel insights into the pathophysiological mechanisms underlying osteoporosis.

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Progressive recruitment of contralesional cortico-reticulospinal pathways drives motor impairment post stroke

Key points

• Activation of the shoulder abductor muscles in the arm opposite a unilateral brain injury causes involuntary increases in elbow, wrist and finger flexion in the same arm, a phenomenon referred to as the flexion synergy.
• It has been proposed that flexion synergy expression is related to reduced output from ipsilesional motor cortex and corticospinal pathways.
• In this human subjects study, we provide evidence that the magnitude of flexion synergy expression is instead related to a progressive, task-dependent recruitment of contralesional cortex.
• We also provide evidence that recruitment of contralesional cortex may induce excessive activation of ipsilateral reticulospinal descending motor pathways that cannot produce discrete movements, leading to flexion synergy expression.
• We interpret these findings as an adaptive strategy that preserves low-level motor control at the cost of fine motor control.

Abstract

A hallmark of hemiparetic stroke is the loss of fine motor control in the contralesional arm and hand and the constraint to a grouped movement pattern known as the flexion synergy. In the flexion synergy, increasing shoulder abductor activation drives progressive, involuntary increases in elbow, wrist and finger flexion. The neural mechanisms underlying this phenomenon remain unclear. Here, across 25 adults with moderate to severe hemiparesis following chronic stroke and 18 adults without neurological injury, we test the overall hypothesis that two inter-related mechanisms are necessary for flexion synergy expression: increased task-dependent activation of the intact, contralesional cortex and recruitment of contralesional motor pathways via ipsilateral reticulospinal projections. First, we imaged brain activation in real time during reaching motions progressively constrained by flexion synergy expression. Using this approach, we found that cortical activity indeed shifts towards the contralesional hemisphere in direct proportion to the degree of shoulder abduction loading in the contralesional arm. We then leveraged the post-stroke reemergence of a developmental brainstem reflex to show that anatomically diffuse reticulospinal motor pathways are active during synergy expression. We interpret this progressive recruitment of contralesional cortico-reticulospinal pathways as an adaptive strategy that preserves low-level motor control at the cost of fine motor control.

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Expanding the histopathological spectrum of CFL2-related myopathies

Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and /or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2^-/- knockout mouse model.

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Performing under pressure: hypertension and the regulation of cerebral oxygen delivery

Abstract

Reductions in arterial oxygen content (CaO₂) elicit increases in cerebral blood flow (CBF) that are adequate to maintain convective delivery of oxygen to the brain in healthy humans (i.e. cerebral oxygen delivery, CDO₂).

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The genetics of aniridia — simple things become complicated

Abstract

Aniridia is a rare, panocular disorder characterized by a variable degree of hypoplasia or the absence of iris tissue associated with additional ocular abnormalities. It is inherited in an autosomal dominant manner, with high penetrance and variable expression even within the same family. In most cases the disease is caused by haploinsufficiency truncating mutations in the PAX6 gene; however, in up to 30% of aniridia patients, disease results from chromosomal rearrangements at the 11p13 region. The aim of this review is to present the clinical and genetic aspects of the disease. Furthermore, we present a molecular diagnostic strategy in the aniridia patients. Recent improvement in the genetic diagnostic approach will precisely diagnosis aniridia patients, which is essential especially for children with aniridia in order to determine the risk of developing a Wilms tumor or neurodevelopmental disorder. Finally, based on the previous studies we describe the current knowledge and latest research findings in the topic of pathogenesis of aniridia and possible future treatment.

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Furthering Our Understanding of Therapist Knowledge and Attitudinal Measurement in Youth Community Mental Health

Abstract

Examining therapist evidence-based practice (EBP) knowledge seems an important step for supporting successful implementation. Advances in implementation science suggest a distinction between practice specific (i.e., knowing which practices are derived from the evidence base) and EBP process (i.e., integrating research evidence, clinical experience, client characteristics, and monitoring outcomes) knowledge. An examination of how these knowledge types are measured and relate to attitudes appears warranted. In our sample of 58 youth community therapists, both practice specific and EBP process knowledge accounted for EBP attitude scores, which varied by therapist demographic variables. Implications for measurement of therapist constructs and future research in identifying therapist predictors of EBP use and youth clinical improvement are discussed.

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Methodological Considerations in Couples’ Fertility Intentions: Missing Men and the Viability of Women’s Proxy Reports

Abstract

Introduction Recent efforts show potential to advance research on unintended childbearing by taking a couple-level approach. However, this work has neither adequately addressed methodological concerns stemming from the challenges associated with male fertility data nor considered the viability of women's proxy reports of fathers intentions. Methods Data from the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B) were used to assess the implications of low response rates among men on couples' unintended childbearing. Then, the accuracy of women's proxy reports of fathers intentions was assessed. Weighted logistic regression analyses were conducted to determine how women's characteristics were associated with men's survey participation whereas weighted multinomial logistic regression analyses were applied to determine how women's characteristics were linked with the accuracy of her proxy report. Results Almost half (46%) of women cannot be matched with data from the child's father, and this discrepancy is most problematic for women who are black, foreign-born, less educated, and unmarried at birth. Women's proxy reports appear viable as 75% of women's reports are consistent with men's responses. Yet, proxy reports underestimate disagreement in couples' intentions as mothers who intended the birth are at an increased risk of "inaccurately" reporting that fathers share their intentions. Discussion Direct approaches to couples' intentions yield privileged samples and systematically omit women at the greatest risk of an unintended birth. However, proxies underestimate disagreement in couples' intentions—a key contribution to the couple approach. Accordingly each approach has its own merits which must be considered in light of specified research questions.

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Maternal Sociodemographic Characteristics, Experiences and Health Behaviors Associated with Postpartum Care Utilization: Evidence from Maryland PRAMS Dataset, 2012–2013

Abstract

Objectives Postpartum visits are increasingly recognized as a window of opportunity for health care providers to counsel new mothers and promote healthy behaviors, including increasing contraceptive use and screening for postpartum depression. In Maryland, there is a lack of research on postpartum visit (PPV) attendance and the specific risk factors associated with not receiving postpartum care. In this study, we estimated the proportion of mothers in Maryland who attended a PPV and assessed maternal sociodemographic characteristics and health behaviors associated with PPV non-attendance. Methods Data were analyzed from the 2012 and 2013 Maryland Pregnancy Risk Assessment Monitoring System (n = 2204). Bivariate and multivariable logistic regression were performed to examine the association between covariates and PPV non-attendance. Results Overall, 89.6% of women reported PPV attendance. Bivariate analyses between maternal sociodemographic and health behavior characteristics and PPV non-attendance indicated that being unmarried (OR 3.03, 95% CI 2.12–4.31), experiencing infant loss (OR 7.17, 95% CI 2.57–19.97), working during pregnancy (OR 0.44, 95% CI 0.31–0.63) and not receiving dental care (OR 2.03, 95% CI 1.43–2.88) as significant risk factors for PPV non-attendance. After controlling for known and theoretical confounders, experiencing an infant loss (aOR 5.18, 95% CI 1.54–17.4), not receiving dental care (aOR 1.54, 95% CI 1.06–2.26) and working during pregnancy (aOR 0.61, 95% CI 0.41–0.93) emerged as strong predictors of PPV non-attendance. Conclusions for Practice Mothers who recently experienced an infant death were at greatest risk for not attending a PPV, suggesting the need to establish comprehensive support networks, including grief counseling and additional service reminders for mothers who experienced an infant death.

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Paediatric genomics: diagnosing rare disease in children

Paediatric genomics: diagnosing rare disease in children

Paediatric genomics: diagnosing rare disease in children, Published online: 19 February 2018; doi:10.1038/nrg.2018.12

Paediatric genomics: diagnosing rare disease in children

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Genetic variation: Putting causal variants on the map

Genetic variation: Putting causal variants on the map

Genetic variation: Putting causal variants on the map, Published online: 19 February 2018; doi:10.1038/nrg.2018.11

Genetic variation: Putting causal variants on the map

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RNA: Follow the SINE for nuclear localization

RNA: Follow the SINE for nuclear localization

RNA: Follow the SINE for nuclear localization, Published online: 19 February 2018; doi:10.1038/nrg.2018.10

RNA: Follow the SINE for nuclear localization

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