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Here we conduct a study involving 12 individuals with retinal dystrophy, neurological impairment, and skeletal abnormalities, with special focus on GPATCH11, a lesser-known G-patch domain-containing protein, regulator of RNA metabolism. To elucidate its role, we study fibroblasts from unaffected individuals and patients carrying the recurring c.328+1 G > T mutation, which specifically removes the main part of the G-patch domain while preserving the other domains. Additionally, we generate a mouse model replicating the patients' phenotypic defects, including retinal dystrophy and behavioral abnormalities. Our results reveal a subcellular localization of GPATCH11 characterized by a diffuse presence in the nucleoplasm, as well as centrosomal localization, suggesting potential functions in RNA and cilia metabolism. Transcriptomic analysis performed on mouse retina detect dysregulation in both gene expression and splicing activity, impacting key processes such as photoreceptor light responses, RNA regulation, and primary cilia-associated metabolism. Proteomic analysis of mouse retina confirms the roles GPATCH11 plays in RNA processing, splicing, and transcription regulation, while also suggesting additional functions in synaptic plasticity and nuclear stress response. Our research provides insights into the diverse roles of GPATCH11 and identifies that the mutations affecting this protein are responsible for a recently characterized described syndrome., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Mitochondrial disorders are characterized by a huge clinical, biochemical, and genetic heterogeneity, which poses significant diagnostic challenges. Several studies report that more than 50% of patients with suspected mitochondrial disease could have a non-mitochondrial disorder. Thus, only the identification of the causative pathogenic variant can confirm the diagnosis. Herein, we describe the diagnostic journey of a family suspected of having a mitochondrial disorder who were referred to our Genetics Department. The proband presented with the association of cerebellar ataxia, COX-negative fibers on muscle histology, and mtDNA deletions. Whole exome sequencing (WES), supplemented by a high-resolution array, comparative genomic hybridization (array-CGH), allowed us to identify two pathogenic variants in the non-mitochondrial SYNE1 gene. The proband and her affected sister were found to be compound heterozygous for a known nonsense variant (c.13258C>T, p.(Arg4420Ter)), and a large intragenic deletion that was predicted to result in a loss of function. To our knowledge, this is the first report of a large intragenic deletion of SYNE1 in patients with cerebellar ataxia (ARCA1). This report highlights the interest in a pangenomic approach to identify the genetic basis in heterogeneous neuromuscular patients with the possible cause of mitochondrial disease. Moreover, even rare copy number variations should be considered in patients with a phenotype suggestive of SYNE1 deficiency.

Ecosystems provide many services that are essential for human activities and for our well-being. Many regulation services are interconnected and are fundamental in mitigating and hindering the negative effects of several phenomena such as pollution. Pollution, in particular airborne particulate matter (PM), represents an important risk to human health. This perspective aims at providing a current framework that relates ecosystem services, regulating services, pollination, and human health, with particular regards to pollution and its impacts. A quantitative literature analysis on the topic has been adopted. The health repercussions of problems related to ecosystem services, with a focus on the effects of atmospheric particulate matter, have been highlighted in the work throughout a case study. In polluted environments, pollinators are severely exposed to airborne PM, which adheres to the insect body hairs and can be ingested through contaminated food resources, i.e., pollen and honey. This poses a serious risk for the health of pollinators with consequences on the pollination service and, ultimately, for human health.

The concept of ecosystem services is widely understood as the services and benefits thatecosystems provide to humans, and they have been categorised into provisioning, regulating, supporting, and cultural services. This article aims to provide an updated overview of the benefits that the honey bee Apis mellifera provides to humans as well as ecosystems. We revised the role of honey bees as pollinators in natural ecosystems to preserve and restore the local biodiversity of wild plants; in agro-ecosystems, this species is widely used to enhance crop yield and quality, meeting the increasing food demand. Beekeeping activity provides humans not only with high-quality food but also with substances used as raw materials and in pharmaceuticals, and in polluted areas, bees convey valuable information on the environmental presence of pollutants and their impact on human and ecosystem health. Finally, the role of the honey bee in symbolic tradition, mysticism, and the cultural values of the bee habitats are also presented. Overall, we suggest that the symbolic value of the honey bee is the most important role played by this insect species, as it may help revitalise and strengthen the intimate and reciprocal relationship between humans and the natural world, avoiding the inaccuracy of considering the ecosystems as mere providers of services to humans.

Ephrin receptor and their ligands, the ephrins, are widely expressed in the developing brain. They are implicated in several developmental processes that are crucial for brain development. Deletions in genes encoding for members of the Eph/ephrin receptor family were reported in several neurodevelopmental disorders. The ephrin receptor A7 gene (EPHA7) encodes a member of ephrin receptor subfamily of the protein-tyrosine kinase family. EPHA7 plays a role in corticogenesis processes, determines brain size and shape, and is involved in development of the central nervous system. One patient only was reported so far with a de novo deletion encompassing EPHA7 in 6q16.1. We report 12 additional patients from nine unrelated pedigrees with similar deletions. The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance. Four patients had tiny deletions involving only EPHA7, suggesting a critical role of EPHA7 in a neurodevelopmental disability phenotype. We provide further evidence for EPHA7 deletion as a risk factor for neurodevelopmental disorder and delineate its clinical phenotype., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Biodiversity strengthens the productivity of any ecosystem (agricultural land, forest, lake, etc.). The loss of biodiversity contributes to food and energy insecurity; increases vulnerability to natural disasters, such as floods or tropical storms; and decreases the quality of both life and health. Wild and managed bees play a key role in maintaining the biodiversity and in the recovery and restoration of degraded habitats. The novelty character of this perspective is to give an updated representation of bee products' biodiversity, sustainability, and health relationship. The role of bees as bioindicators, their importance in the conservation of biodiversity, their ecosystem services, and the variety of the bee products are described herein. An overview of the main components of bee products, their biological potentials, and health is highlighted and detailed as follows: (i) nutritional value of bee products, (ii) bioactive profile of bee products and the related beneficial properties; (iii) focus on honey and health through a literature quantitative analysis, and (iv) bee products explored through databases. Moreover, as an example of the interconnection between health, biodiversity, and sustainability, a case study, namely the "Cellulose Park", realized in Rome (Italy), is presented here. This case study highlights how bee activities can be used to assess and track changes in the quality of agricultural ecosystems-hive products could be valid indicators of the quality and health of the surrounding environment, as well as the changes induced by the biotic and abiotic factors that impact the sustainability of agricultural production and biodiversity conservation in peri-urban areas.

Background: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies., Methods: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA., Results: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption ( KANSL1 , FOXP1 , SPRED1 , TLK2 , MBD5 , DMD , AUTS2 , MEIS2 , MEF2C , NRXN1 , NFIX , SYNGAP1, GHR, ZMIZ1 ) and 7 by position effect ( DLX5 , MEF2C , BCL11B , SATB2, ZMIZ1 ). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation., Conclusion: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Congenital heart defects (CHDs) may be isolated or associated with other malformations. The use of chromosome microarray (CMA) can increase the genetic diagnostic yield for CHDs by between 4% and 10%. The objective of this study was to evaluate the value of CMA after the prenatal diagnosis of an isolated CHD., Methods: In a retrospective, nationwide study performed in France, we collected data on all cases of isolated CHD that had been explored using CMAs in 2015., Results: A total of 239 fetuses were included and 33 copy number variations (CNVs) were reported; 19 were considered to be pathogenic, six were variants of unknown significance, and eight were benign variants. The anomaly detection rate was 10.4% overall but ranged from 0% to 16.7% as a function of the isolated CHD in question. The known CNVs were 22q11.21 deletions (n = 10), 22q11.21 duplications (n = 2), 8p23 deletions (n = 2), an Alagille syndrome (n = 1), and a Kleefstra syndrome (n = 1)., Conclusion: The additional diagnostic yield was clinically significant (3.1%), even when anomalies in the 22q11.21 region were not taken into account. Hence, patients with a suspected isolated CHD and a normal karyotype must be screened for chromosome anomalies other than 22q11.21 duplications and deletions., (© 2019 John Wiley & Sons, Ltd.)

Background: Since the advent of next generation sequencing (NGS), several studies have tried to evaluate the relevance of targeted gene panel sequencing and whole exome sequencing for molecular diagnosis of mitochondrial diseases. The comparison between these different strategies is extremely difficult. A recent study analysed a cohort of patients affected by a mitochondrial disease using a NGS approach based on a targeted gene panel including 132 genes. This strategy led to identify the causative mutations in 15.2% of cases. The number of novel genes responsible for respiratory chain deficiency increases very rapidly., Methods: In order to determine the impact of larger panels used as a first screening strategy on molecular diagnosis success, we analysed a cohort of 80 patients affected by a mitochondrial disease with a first mitochondrial DNA (mtDNA) NGS screening and secondarily a targeted mitochondrial panel of 281 nuclear genes., Results: Pathogenic mtDNA abnormalities were identified in 4.1% (1/24) of children and 25% (14/56) of adult patients. The remaining 65 patients were analysed with our targeted mitochondrial panel and this approach enabled us to achieve an identification rate of 21.7% (5/23) in children versus 7.1% (3/42) in adults., Conclusions: Our results confirm that larger gene panels do not improve diagnostic yield of mitochondrial diseases due to (i) their very high genetic heterogeneity, (ii) the ongoing discovery of novel genes and (iii) mutations in genes apparently not related to mitochondrial function that lead to secondary respiratory chain deficiency.

CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)