AUTS2-related Syndrome: Insights from a large European cohort.

Purpose: AUTS2-related syndrome is a condition characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters AUTS2 encodes two distinct long and short isoforms encoding a putative transcriptional activator.

Methods: Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2- related syndrome cohort of 58 patients harboring genomic rearrangements or single nucleotide variants (SNVs).

Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis.

Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERF and showing a phenotype reminiscent of NS.

Cost-Effectiveness of Whole-Genome vs Whole-Exome Sequencing Among Children With Suspected Genetic Disorders.

Importance: The diagnosis of rare diseases and other genetic conditions can be daunting due to vague or poorly defined clinical features that are not recognized even by experienced clinicians. Next-generation sequencing technologies, such as whole-genome sequencing (WGS) and whole-exome sequencing (WES), have greatly enhanced the diagnosis of genetic diseases by expanding the ability to sequence a large part of the genome, rendering a cost-effectiveness comparison between them necessary.

Objective: To assess the cost-effectiveness of WGS compared with WES and conventional testing in children with suspected genetic disorders.

Robert J. Gorlin: Personal Memory of a Friend and Mentor in Clinical Genetics.

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Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1.

Bayesian cost-effectiveness analysis of Whole genome sequencing versus Whole exome sequencing in a pediatric population with suspected genetic disorders.

Genetic diseases are medical conditions caused by sequence or structural changes in an individual's genome. Whole exome sequencing (WES) and whole genome sequencing (WGS) are increasingly used for diagnosing suspected genetic conditions in children to reduce the diagnostic delay and accelerating the implementation of appropriate treatments. While more information is becoming available on clinical efficacy and economic sustainability of WES, the broad implementation of WGS is still hindered by higher complexity and economic issues.

Williams-Beuren syndrome shapes the gut microbiota metaproteome.

Williams-Beuren syndrome (WBS) is a rare genetic neurodevelopmental disorder with multi-systemic manifestations. The evidence that most subjects with WBS face gastrointestinal (GI) comorbidities, have prompted us to carry out a metaproteomic investigation of their gut microbiota (GM) profile compared to age-matched healthy subjects (CTRLs). Metaproteomic analysis was carried out on fecal samples collected from 41 individuals with WBS, and compared with samples from 45 CTRLs.

Association between exposure to wind turbines and sleep disorders: A systematic review and meta-analysis.

To date, there is scarce evidence on the association between sleep disorders and noise generated by wind turbines. We searched six relevant electronic databases from the inception to May 2023 for relevant articles. The methodological quality of the included articles was evaluated using the US National Institutes of Health tool.

Organizational Aspects of the Implementation and Use of Whole Genome Sequencing and Whole Exome Sequencing in the Pediatric Population in Italy: Results of a Survey.

This study explores the organizational aspects of whole genome sequencing (WGS) implementation for pediatric patients with suspected genetic disorders in Italy, comparing it with whole exome sequencing (WES). Health professionals' opinions were collected through an internet-based survey and analyzed using a qualitative summative content analysis methodology. Among the 16 respondents, most were clinical geneticists performing only WES, while 5 also used WGS.

Whole genome sequencing diagnostic yield for paediatric patients with suspected genetic disorders: systematic review, meta-analysis, and GRADE assessment.

Background: About 80% of the roughly 7,000 known rare diseases are single gene disorders, about 85% of which are ultra-rare, affecting less than one in one million individuals. NGS technologies, in particular whole genome sequencing (WGS) in paediatric patients suffering from severe disorders of likely genetic origin improve the diagnostic yield allowing targeted, effective care and management. The aim of this study is to perform a systematic review and meta-analysis to assess the effectiveness of WGS, with respect to whole exome sequencing (WES) and/or usual care, for the diagnosis of suspected genetic disorders among the paediatric population.

FOXI3 pathogenic variants cause one form of craniofacial microsomia.

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown.

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing.

Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned.

Clinical variability in DYNC2H1-related skeletal ciliopathies includes Ellis-van Creveld syndrome.

Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins.

Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish.

Vesicle biogenesis, trafficking and signaling via Endoplasmic reticulum-Golgi network support essential developmental processes and their disruption lead to neurodevelopmental disorders and neurodegeneration. We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation. Microcephaly-associated ARF3 variants affect residues within the guanine nucleotide binding pocket and variably perturb protein stability and GTP/GDP binding.

A Complex Genomic Rearrangement Resulting in Loss of Function of and in a Patient with Severe Developmental and Epileptic Encephalopathy.

Complex genomic rearrangements (CGRs) are structural variants arising from two or more chromosomal breaks, which are challenging to characterize by conventional or molecular cytogenetic analysis (karyotype and FISH). The integrated approach of standard and genomic techniques, including optical genome mapping (OGM) and genome sequencing, is crucial for disclosing and characterizing cryptic chromosomal rearrangements at high resolutions. We report on a patient with a complex developmental and epileptic encephalopathy in which karyotype analysis showed a de novo balanced translocation involving the long arms of chromosomes 2 and 18.

Delineation of the clinical profile of CNOT2 haploinsufficiency and overview of the IDNADFS phenotype.

CNOT2 haploinsufficiency underlies a rare neurodevelopmental disorder named Intellectual Developmental disorder with NAsal speech, Dysmorphic Facies, and variable Skeletal anomalies (IDNADFS, OMIM 618608). The condition clinically overlaps with chromosome 12q15 deletion syndrome, suggesting a major contribution of CNOT2 haploinsufficiency to the latter. CNOT2 is a member of the CCR4-NOT complex, which is a master regulator of multiple cellular processes, including gene expression, RNA deadenylation, and protein ubiquitination.

Teleost Fish and Organoids: Alternative Windows Into the Development of Healthy and Diseased Brains.

The variety in the display of animals' cognition, emotions, and behaviors, typical of humans, has its roots within the anterior-most part of the brain: the forebrain, giving rise to the neocortex in mammals. Our understanding of cellular and molecular events instructing the development of this domain and its multiple adaptations within the vertebrate lineage has progressed in the last decade. Expanding and detailing the available knowledge on regionalization, progenitors' behavior and functional sophistication of the forebrain derivatives is also key to generating informative models to improve our characterization of heterogeneous and mechanistically unexplored cortical malformations.

Organ donation from patients with a rare disease is often safe: the italian guidelines.

Although a disease is defined as rare when it has a prevalence of less than 1:2000, the overall prevalence of rare diseases in the population is greater than 1%. Among potential organ donors, a similar frequency is observed. To date, guidelines have not been established, and operational decisions have been made empirically, case- by-case, based on the experience and expertise of clinicians.

Intragenic inversions in NF1 gene as pathogenic mechanism in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1), an autosomal dominant disorder characterized by skin pigmentary lesions and multiple cutaneous neurofibromas, is caused by neurofibromin 1 (NF1) loss of function variants. Currently, a molecular diagnosis is frequently established using a multistep protocol based on cDNA and gDNA sequence analysis and/or Multiplex Ligation-dependent Probe Amplification (MLPA) assay on genomic DNA, providing an overall detection rate of about 95-97%. The small proportion of clinically diagnosed patients, which at present do not obtain a molecular confirmation likely are mosaic, as their pathogenic variant may remain undetected due to low sensitivity of low coverage NGS approaches, or they may carry a type of pathogenic variant refractory to currently used technologies.

Complex Presentation of Hao-Fountain Syndrome Solved by Exome Sequencing Highlighting Co-Occurring Genomic Variants.

Objective: The co-occurrence of pathogenic variants has emerged as a relatively common finding underlying complex phenotypes. Here, we used whole-exome sequencing (WES) to solve an unclassified multisystem clinical presentation.

Patients And Methods: A 20-year-old woman affected by moderate intellectual disability (ID), dysmorphic features, hypertrichosis, scoliosis, recurrent bronchitis, and pneumonia with bronchiectasis, colelithiasis, chronic severe constipation, and a family history suggestive of autosomal dominant recurrence of polycystic kidney disease was analyzed by WES to identify the genomic events underlying the condition.

Case Report: Precision COVID-19 Immunization Strategy to Overcome Individual Fragility: A Case of Generalized Lipodystrophy Type 4.

A 48-year-old patient affected with congenital generalized lipodystrophy type 4 failed to respond to two doses of the BNT162b2 vaccine, consisting of lipid nanoparticle encapsulated mRNA. As the disease is caused by biallelic variants of , a molecule indispensable for lipid endocytosis and regulation, we complemented the vaccination cycle with a single dose of the Ad26.COV2 vaccine.