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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