Prenatal diagnosis following preimplantation genetic testing (PGT): recommendations of the Italian Society of Human Genetics (SIGU).

This document aims to provide good practice recommendations in order to support maternal-foetal medicine specialists, clinical geneticists and clinical laboratory geneticists in the management of pregnancies obtained after the transfer of an embryo tested with preimplantation genetic testing (PGT). It was drafted by geneticists expert in preimplantation genetics and prenatal genetic diagnosis belonging to the "Working Group in Cytogenomics, Prenatal and Reproductive Genetics" of the "Italian Society of Human Genetics" (SIGU). In particular, the paper addresses the diagnostic algorithm to be applied in prenatal follow-up depending on the type of PGT performed, the results obtained and the related diagnostic value based on the most recent literature data and Italian and international recommendations.

Cardiac Involvement and TBCK-Related Neurodevelopmental Disorder: Is It a New Feature of This Condition?

TBCK (TBC1 Domain-Containing Kinase) encodes a protein playing a role in actin organization and cell growth/proliferation via the mTOR signaling pathway. Deleterious biallelic TBCK variants cause Hypotonia, infantile, with psychomotor retardation and characteristic facies 3. We report on three affected sibs, also displaying cardiac malformations.

Two Novel Biallelic Variants in the Gene: The First Italian Case and a Literature Review.

: The gene encodes for the catalytic α subunit of Cytoplasmic phenylalanine-tRNA synthetase (FARS1), an essential enzyme for protein biosynthesis in transferring its amino acid component to tRNAs. Biallelic pathogenic variants have been associated with a multisystemic condition, characterized by variable expressivity and incomplete penetrance. Here, we report the case of an 11 year-old girl presenting interstitial lung disease, supratentorial leukoencephalopathy with brain cysts, hepatic dysfunction, hypoalbuminemia, skin and joint hyperlaxity, growth retardation, and dysmorphic features.

Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome's clinical and molecular spectrum through NALCN structural analysis.

Introduction: Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1, MIM#615419) is a rare, birth onset, autosomal recessive disorder caused by homozygous or compound heterozygous truncating variants in gene (MIM#611549) resulting in a loss-of-function effect.

Methods: We enrolled a new IHPRF1 patients' cohort in the framework of an international multicentric collaboration study. Using specialized pathogenicity predictors and structural analyses, we assessed the mechanistic consequences of the deleterious variants retrieved on NALCN structure and function.

is implicated in central nervous system, orofacial and maxillofacial anomalies.

Background: Previous studies in mouse, and zebrafish embryos show strong expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the role of human transcription factor activator protein 2 ( in human embryonic central nervous system (CNS), orofacial and maxillofacial development is unknown.

Methods: Through a collaborative work, exome survey was performed in families with congenital CNS, orofacial and maxillofacial anomalies.

Molecular and clinical Insights into KMT2E-Related O'Donnell-Luria-Rodan syndrome in a novel patient cohort.

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant neurodevelopmental disorder mainly characterized by global development delay/intellectual disability, white matter abnormalities, and behavioral manifestations. It is caused by pathogenic variants in the KMT2E gene. Here we report seven new patients with loss-of-function KMT2E variants, six harboring frameshift/nonsense changes, and one with a 7q22.

Structural and functional alterations of neurons derived from sporadic Alzheimer's disease hiPSCs are associated with downregulation of the LIMK1-cofilin axis.

Background: Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of pathological proteins and synaptic dysfunction. This study aims to investigate the molecular and functional differences between human induced pluripotent stem cells (hiPSCs) derived from patients with sporadic AD (sAD) and age-matched controls (healthy subjects, HS), focusing on their neuronal differentiation and synaptic properties in order to better understand the cellular and molecular mechanisms underlying AD pathology.

Methods: Skin fibroblasts from sAD patients (n = 5) and HS subjects (n = 5) were reprogrammed into hiPSCs using non-integrating Sendai virus vectors.

Sex-Specific HLA Alleles Contribute to the Modulation of COVID-19 Severity.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, responsible for Coronavirus Disease 2019 (COVID-19), exhibits a spectrum of clinical manifestations, ranging from asymptomatic to severe pulmonary dysfunction or death. The variability in COVID-19 severity has largely been attributed to the host's genetic characteristics, suggesting a polygenic genetic architecture, without significant strong evidence of sex-related genetic differences. In this Italian retrospective case-control study, we investigated the association between COVID-19 severity (severe vs.

Heterozygous variants disrupting the interaction of ERF with activated ERK1/2 cause microcephaly, developmental delay, and skeletal anomalies.

Heterozygous deleterious null alleles and specific missense variants in the DNA-binding domain of the ETS2 repressor factor (ERF) cause craniosynostosis, while the recurrent p.(Tyr89Cys) missense variant is associated with Chitayat syndrome. Exome and whole transcriptome sequencing revealed the ERF de novo in-frame indel c.

Unveiling genetic insights: Array-CGH and WES discoveries in a cohort of 122 children with essential autism spectrum disorder.

Background: Autistic Spectrum Disorder (ASD) is a neurodevelopmental disorder with a strong genetic component and high heterogeneity. Essential ASD refers to patients who do not have other comorbidities. This study aimed to investigate the genetic basis of essential ASD using whole exome sequencing (WES) and array-comparative genomic hybridization (array-CGH).

Copy Number Variants in Cardiac Channelopathies: Still a Missed Part in Routine Arrhythmic Diagnostics.

Inherited cardiac channelopathies are major causes of sudden cardiac death (SCD) in young people. Genetic testing is focused on the identification of single-nucleotide variants (SNVs) by Next-Generation Sequencing (NGS). However, genetically elusive cases can carry copy number variants (CNVs), which need specific detection tools.

Huppke-Brendel syndrome: Novel cases and a therapeutic trial with ketogenic diet and N-acetylcysteine.

Huppke-Brendel syndrome (HBS) is an autosomal recessive disorder caused by mutations, a gene coding for the acetyl-CoA transporter-1 (AT-1). So far it has been described in nine pediatric and one adult patient. Therapeutic trials with copper histidinate failed to achieve any clinical improvement.

Regulation of BCR-dependent germinal center B-cell formation by HGAL and insight into its emerging myeloid ortholog, C1ORF150.

The specificity of cytokine and immunoreceptor signaling frequently depends upon receptor recruitment of select adaptor proteins and specifically engaged effectors. This review focuses on the orthologous adaptor proteins, HGAL and C1ORF150, and aims to provide insight into their respective modulation of lymphoid and myeloid cell signaling, formation, and function. HGAL acts predominantly within germinal center B cells as an important BCR signal transducer.

Evaluating deep learning techniques for optimal neurons counting and characterization in complex neuronal cultures.

The counting and characterization of neurons in primary cultures have long been areas of significant scientific interest due to their multifaceted applications, ranging from neuronal viability assessment to the study of neuronal development. Traditional methods, often relying on fluorescence or colorimetric staining and manual segmentation, are time consuming, labor intensive, and prone to error, raising the need for the development of automated and reliable methods. This paper delves into the evaluation of three pivotal deep learning techniques: semantic segmentation, which allows for pixel-level classification and is solely suited for characterization; object detection, which focuses on counting and locating neurons; and instance segmentation, which amalgamates the features of the other two but employing more intricate structures.

Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder.

DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case-series of 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants in DDX17. All 11 patients in our case series had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated.

De Novo GRID2 Variant as a Cause of Ataxia with Oculomotor Apraxia and Alpha-Fetoprotein Elevation.

Bi-allelic pathogenic variants in GRID2 have been initially associated to an autosomal recessive form of spinocerebellar ataxia, namely SCAR18. Subsequently, few monoallelic cases have been described. Here we present a new subject harboring a novel de novo heterozygous GRID2 missense variant presenting with progressive ataxia together with cerebellar atrophy and, for the first time, alpha-fetoprotein (AFP) elevation.

Exploring heterogeneity in coxarthrosis medication use patterns before total hip replacement: a State Sequence Analysis.

Objective: Evidence of geographical variation in total hip replacement (THR) and deviations from treatment guidelines persists. In this exploratory study, we aim to gain an in-depth understanding of patients' healthcare trajectories by identifying and visualising medication use patterns in coxarthrosis patients before surgery. We examine their association with patient characteristics and THR, and compare them with recommendations on mild analgesics, opioid prescription and exhaustion of conservative therapy.

Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.

Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.

Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals.

Observational evidence reveals the significance of nocturnal chemistry in seasonal secondary organic aerosol formation.

Oxidized Organic Aerosol (OOA), a major component of fine atmospheric particles, impacts climate and human health. Previous experiments and atmospheric models emphasize the importance of nocturnal OOA formation from NO· oxidation of biogenic VOCs. This seasonal study extends the understanding by showing that nocturnal oxidation of biomass-burning emissions can account for up to half of total OOA production in fall and winter.

Biallelic NEXN variants and fetal onset dilated cardiomyopathy: two independent case reports and revision of literature.

Background: Dilated cardiomyopathy (DCM) is an etiologically heterogeneous group of diseases of the myocardium. With the rapid evolution in laboratory investigations, genetic background is increasingly determined including many genes with variable penetrance and expressivity. Biallelic NEXN variants are rare in humans and associated with poor prognosis: fetal and perinatal death or severe DCMs in infants.

POLR3B de novo variants are a rare cause of infantile myoclonic epilepsy.

Purpose: To report on a new phenotype in a patient carrying a novel, undescribed de novo variant in POLR3B, affected by generalized myoclonic epilepsy and neurodevelopmental disorder, without neuropathy. It is known that biallelic pathogenic variants in POLR3B cause hypomyelinating leukodystrophy-8, and heterozygous de novo variants are described in association to a phenotype characterized by predominantly demyelinating sensory-motor peripheral neuropathy, ataxia, spasticity, intellectual disability and epilepsy, in which the peripheral neuropathy is often the main clinical presentation.

Methods: We collected clinical, electrophysiological and neuroimaging data from the affected subject and performed a Trio-Clinical Exome Sequencing.

Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules.

Purpose: Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs).

Methods: A total of 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing.