Retinal Degeneration Diagnosed at 12 and 13 Months and Sensorineural Hearing Loss in Two Unrelated Female Infants With PRS Deficiency.

Phosphoribosyl pyrophosphate synthetase (PRS) deficiency, an X-linked condition caused by loss-of-function variants in PRPS1, manifests as a phenotypic continuum encompassing three previously distinct disorders: Arts syndrome, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and X-linked nonsyndromic sensorineural hearing loss (DFNX1). Males are typically more severely affected, while females with the same variant often present with milder forms. We report two unrelated female patients with progressive sensorineural hearing loss and very early-onset retinal degeneration, at 12 and 13 months, respectively, and a pathogenic PRPS1 c.

A New GlyT2 Variant Associated with Hyperekplexia.

Hyperekplexia (OMIM 149400), a sensorimotor syndrome of perinatal clinical relevance, causes newborns to display an energic startle reflex in response to certain trivial stimuli. This condition can be lethal due to apnea episodes. The disease is caused by a blockade of glycinergic neurotransmission.

The cochlear basal turn as a very preserved region in cochlear hypoplasias: radiological and embryological considerations from a cohort of 125 patients.

Purpose: A distinct form of cochlear hypoplasia, characterized by the preservation of the first half of the basal turn with hypoplastic and anteriorly displaced upper turns, was historically associated with branchio-oto-renal (BOR) syndrome, but can also occur in other genetic, syndromic and non-syndromic causes of hearing loss. This study aims to describe this phenotype with relative preservation of the basal turn, particularly its first half, in a significant proportion of cochlear hypoplasia cases due to different causes.

Methods: We retrospectively reviewed temporal bone imaging from 125 patients (250 ears) with cochlear malformations from a tertiary pediatric center, focusing on cases where the basal turn was partially or completely preserved.

Experimental Evaluation of Zinc and Copper Terrestrial Ecotoxicity Prediction by Life Cycle Assessment in Agricultural Recycling of Livestock Effluent.

The agronomic benefits of organic waste application on farmland can be overshadowed by the potential health and environmental impacts associated with trace element emissions, especially copper (Cu) and zinc (Zn). This has prompted a need for life cycle assessment (LCA) models to predict their terrestrial comparative toxicity potential () and impact score. We compared the LCA (reference method) prediction ability with that obtained with an experimental data set obtained from a month-long incubation experiment (experimental method) on a soil amended or not with 31 livestock effluents mimicking agronomically relevant scenarios.

Incomplete partition type II in its various manifestations: isolated, in association with EVA, syndromic, and beyond; a multicentre international study.

Purpose: Incomplete partition type II (IP-II) is characterized by specific histological features and radiological appearance. It may occur in isolation or in association with an enlarged vestibular aqueduct (EVA). Among those with IP-II and EVA, a subset has a diagnosis of Pendred syndrome.

Preparing for Otoferlin gene therapy trials: A survey of NHS Paediatric Audiology and Cochlear Implant services on diagnosis and management of Auditory Neuropathy Spectrum Disorder.

Objectives: Gene therapy for monogenic hearing loss is on the horizon. The first trials in patients with Auditory Neuropathy Spectrum Disorder (ANSD) due to pathogenic variants in the Otoferlin (OTOF) gene will open this year. In the UK, the new NHS Genomic Medicine Service (GMS) offers genetic testing in each child diagnosed with congenital or early onset sensorineural hearing loss.

A novel ELP1 mutation impairs the function of the Elongator complex and causes a severe neurodevelopmental phenotype.

Background: Neurodevelopmental disorders (NDDs) are heterogeneous, debilitating conditions that include motor and cognitive disability and social deficits. The genetic factors underlying the complex phenotype of NDDs remain to be elucidated. Accumulating evidence suggest that the Elongator complex plays a role in NDDs, given that patient-derived mutations in its ELP2, ELP3, ELP4 and ELP6 subunits have been associated with these disorders.

Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5.

Mixed-methods evaluation of the NHS Genomic Medicine Service for paediatric rare diseases: study protocol.

Background: A new nationally commissioned NHS England Genomic Medicine Service (GMS) was recently established to deliver genomic testing with equity of access for patients affected by rare diseases and cancer. The overarching aim of this research is to evaluate the implementation of the GMS during its early years, identify barriers and enablers to successful implementation, and provide recommendations for practice. The focus will be on the use of genomic testing for paediatric rare diseases.

Critical Review: Role of Inorganic Nanoparticle Properties on Their Foliar Uptake and Translocation.

There is increasing pressure on global agricultural systems due to higher food demand, climate change, and environmental concerns. The design of nanostructures is proposed as one of the economically viable technological solutions that can make agrochemical use (fertilizers and pesticides) more efficient through reduced runoff, increased foliar uptake and bioavailability, and decreased environmental impacts. However, gaps in knowledge about the transport of nanoparticles across the leaf surface and their behavior limit the rational design of nanoparticles for foliar delivery with controlled fate and limited risk.

Persistently elevated CK and lysosomal storage myopathy associated with mucolipin 1 defects.

Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder caused by bi-allelic pathogenic variants in the gene MCOLN1. This encodes for mucolipin-1 (ML1), an endo-lysosomal transmembrane Ca channel involved in vesicular trafficking. Although experimental models suggest that defects in mucolipin-1 can cause muscular dystrophy, putatively due to defective lysosomal-mediated sarcolemma repair, the role of mucolipin-1 in human muscle is still poorly deciphered.

Syndromic Forms of Hyperinsulinaemic Hypoglycaemia-A 15-year follow-up Study.

Objective: Hyperinsulinaemic hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in children. The molecular basis includes defects in pathways that regulate insulin release. Syndromic conditions like Beckwith-Wiedemann (BWS), Kabuki (KS) and Turner (TS) are known to be associated with a higher risk for HH.

Delivering genome sequencing for rapid genetic diagnosis in critically ill children: parent and professional views, experiences and challenges.

Rapid genomic sequencing (RGS) is increasingly being used in the care of critically ill children. Here we describe a qualitative study exploring parent and professional perspectives around the usefulness of this test, the potential for unintended harms and the challenges for delivering a wider clinical service. The Rapid Paediatric Sequencing (RaPS) study offered trio RGS for diagnosis of critically ill children with a likely monogenic disorder.

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders.

The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO.

Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease.

We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome sequencing in family 1 and exome sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4',5'-phosphate (cyclic FMN) through an FMN lyase domain.

Protein coating composition targets nanoparticles to leaf stomata and trichomes.

Plant nanobiotechnology has the potential to revolutionize agriculture. However, the lack of effective methods to deliver nanoparticles (NPs) to the precise locations in plants where they are needed impedes these technological innovations. Here, model gold nanoparticles (AuNP) were coated with citrate, bovine serum albumin (BSA) as a protein control, or LM6-M, an antibody with an affinity for functional groups unique to stomata on leaf surfaces to deliver the AuNPs to stomata.

Contribution of retrotransposition to developmental disorders.

Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands.

Persistent hyperinsulinaemic hypoglycaemia in children with Rubinstein-Taybi syndrome.

Objective: Genetic aetiology remains unknown in up to 50% of patients with persistent hyperinsulinaemic hypoglycaemia (HH). Several syndromes are associated with HH. We report Rubinstein-Taybi syndrome (RSTS) as one of the possible causes of persistent HH.

PIGT-CDG, a disorder of the glycosylphosphatidylinositol anchor: description of 13 novel patients and expansion of the clinical characteristics.

Purpose: To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perform genotype-phenotype correlation, and to investigate the onset and severity of the epilepsy associated with the different genetic subtypes of this rare disorder. Furthermore, to use computer-assisted facial gestalt analysis in PIGT-CDG and to the compare findings with other glycosylphosphatidylinositol (GPI) anchor deficiencies.

Methods: We evaluated 13 children from eight unrelated families with homozygous or compound heterozygous pathogenic variants in PIGT.

Sotos Syndrome Presenting with Neonatal Hyperinsulinaemic Hypoglycaemia, Extensive Thrombosis, and Multisystem Involvement.

Initially described as an uncommon presenting feature of Sotos syndrome (SoS), over the last decades, congenital hyperinsulinaemic hypoglycaemia (CHI) has been increasingly reported in association with this condition. The mechanism responsible for CHI in SoS is unclear. We report the case of a neonate presenting with CHI and extensive venous and arterial thrombosis associated with kidney, heart, liver, skeleton, and brain abnormalities and finally diagnosed with SoS on whole genome sequencing.

Rapid Paediatric Sequencing (RaPS): comprehensive real-life workflow for rapid diagnosis of critically ill children.

Background: Rare genetic conditions are frequent risk factors for, or direct causes of, paediatric intensive care unit (PICU) admission. Such conditions are frequently suspected but unidentified at PICU admission. Compassionate and effective care is greatly assisted by definitive diagnostic information.