A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease.

Copy number variation (CNV) of the amyloid-β precursor protein gene (APP) is a known cause of autosomal dominant Alzheimer disease (ADAD), but de novo genetic variants causing ADAD are rare. We report a mother and daughter with neuropathologically confirmed definite Alzheimer disease (AD) and extensive cerebral amyloid angiopathy (CAA). Copy number analysis identified an increased number of APP copies and genome sequencing (GS) revealed the underlying complex genomic rearrangement (CGR) including a triplication of APP with two unique breakpoint junctions (BPJs).

Acute Vestibular Syndrome Unmasking an -Spectrum Disorder.

Objectives: Since the discovery of biallelic pentanucleotide expansions in as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome, a wide and growing clinical spectrum has emerged. In this article, we report a man with acute vestibular syndrome that likely unmasked a -spectrum disorder.

Methods: Detailed clinical evaluation, neuroimaging, nerve conduction studies, evaluation of vestibular function, and short-read whole-genome sequencing and targeted long-read adaptive sequencing were performed.

Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression.

Background: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.

A combination of long- and short-read genomics reveals frequent p-arm breakpoints within chromosome 21 complex genomic rearrangements.

Purpose: Although chromosome 21 is the smallest human chromosome, it is highly relevant in the pathogenicity of both cancer and congenital diseases, including Alzheimer disease and trisomy 21 (Down syndrome). In addition, cases with rare structural variants (SVs) of chromosome 21 have been reported. These events vary in size and include large chromosomal events, such as ring chromosomes and small partial aneuploidies.

The value of age of onset and family history as predictors of molecular diagnosis in a Swedish cohort of inherited retinal disease.

Purpose: This study aimed to characterize clinical and genetic findings in a Swedish cohort with inherited retinal disease (IRD), identify predictors for achieving a molecular diagnosis and evaluate the effects of increased genetic testing over time.

Methods: Clinical and genetic data from 324 nonrelated IRD index individuals referred for genetic testing in the Stockholm region between 2016 and 2023 were collected retrospectively and analysed by clinical subtype, age of onset and testing period (2016-2020 vs. 2021-2023).

Multi-omics analysis detail a submicroscopic inv(15)(q14q15) generating fusion transcripts and MEIS2 and NUSAP1 haploinsufficiency.

Inversions are balanced structural variants that often remain undetected in genetic diagnostics. We present a female proband with a de novo Chromosome 15 paracentric inversion, disrupting MEIS2 and NUSAP1. The inversion was detected by short-read genome sequencing and confirmed with adaptive long-read sequencing.

Structural Variants in COL1A1 and COL1A2 in Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI) is a heterogeneous skeletal dysplasia characterized by bone fragility, skeletal deformities, and short stature. Most commonly, it is caused by autosomal dominant variants in the type I collagen genes, COL1A1 or COL1A2. Type I collagen is the main protein of the extracellular matrix in the skeleton and changes in its structure or quantity may lead to OI.

Leveraging the T2T assembly to resolve rare and pathogenic inversions in reference genome gaps.

Chromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in Short-read genome sequencing (srGS) can only resolve ∼70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) ( = 9) or srGS ( = 3) and resolve nine of them.

A national long-read sequencing study on chromosomal rearrangements uncovers hidden complexities.

Clinical genetic laboratories often require a comprehensive analysis of chromosomal rearrangements/structural variants (SVs), from large events like translocations and inversions to supernumerary ring/marker chromosomes and small deletions or duplications. Understanding the complexity of these events and their clinical consequences requires pinpointing breakpoint junctions and resolving the derivative chromosome structure. This task often surpasses the capabilities of short-read sequencing technologies.

Seasonal influenza vaccination: A global review of national policies in 194 WHO member states in 2022.

Introduction: Seasonal influenza vaccination prevents severe influenza disease and death. The World Health Organization (WHO) encourages all countries to consider annual seasonal influenza vaccination for health workers, people with chronic conditions, older adults, pregnant women and other high-risk populations as relevant for their national context. This paper provides a global update on the status of countries' influenza vaccination policies and programmes as of December 2022.

Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci.

The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes.

Genome sequencing differentiates a paracentric inversion from a balanced insertion enabling more accurate preimplantation genetic testing.

Introduction: Distinguishing paracentric inversions (PAIs) from chromosomal insertions has traditionally relied on fluorescent in situ hybridization (FISH) techniques, but recent advancements in high-throughput sequencing have enabled the use of genome sequencing for such differentiation. In this study, we present a 38-year-old male carrier of a paracentric inversion on chromosome 2q, inv (2)(q31.2q34), whose partner experienced recurrent miscarriages.

Contribution of vaccination to improved survival and health: modelling 50 years of the Expanded Programme on Immunization.

Background: WHO, as requested by its member states, launched the Expanded Programme on Immunization (EPI) in 1974 to make life-saving vaccines available to all globally. To mark the 50-year anniversary of EPI, we sought to quantify the public health impact of vaccination globally since the programme's inception.

Methods: In this modelling study, we used a suite of mathematical and statistical models to estimate the global and regional public health impact of 50 years of vaccination against 14 pathogens in EPI.

Long-read sequencing and optical mapping generates near T2T assemblies that resolves a centromeric translocation.

Long-read genome sequencing (lrGS) is a promising method in genetic diagnostics. Here we investigate the potential of lrGS to detect a disease-associated chromosomal translocation between 17p13 and the 19 centromere. We constructed two sets of phased and non-phased de novo assemblies; (i) based on lrGS only and (ii) hybrid assemblies combining lrGS with optical mapping using lrGS reads with a median coverage of 34X.

COVID-19 Vaccination Coverage - World Health Organization African Region, 2021-2023.

With the availability of authorized COVID-19 vaccines in early 2021, vaccination became an effective tool to reduce COVID-19-associated morbidity and mortality. Initially, the World Health Organization (WHO) set an ambitious target to vaccinate 70% of the global population by mid-2022. However, in July 2022, WHO recommended that all countries, including those in the African Region, prioritize COVID-19 vaccination of high-risk groups, including older adults and health care workers, to have the greatest impact on morbidity and mortality.

A Practical Guide to Full Value of Vaccine Assessments.

Articulating the wide range of health, social and economic benefits that vaccines offer may help to overcome obstacles in the vaccine development pipeline. A framework to guide the assessment and communication of the value of a vaccine-the Full Value of Vaccine Assessment (FVVA)-has been developed by the WHO. The FVVA framework offers a holistic assessment of the value of vaccines, providing a synthesis of evidence to inform the public health need of a vaccine, describing the supply and demand aspects, its market and its impact from a health, financial and economic perspective.

Key Learnings from the Development and Early Use of Global Guidance on the Integration of COVID-19 Vaccination into Broader Health Systems.

More than 13.5 billion COVID-19 vaccine doses were delivered between 2021 and 2023 through a mix of delivery platforms, with mass vaccination campaigns being the main approach. In 2022, with the continued circulation of SARS-CoV2 and the need for periodic boosters being most likely, countries were required to plan for more sustainable approaches to provide COVID-19 vaccinations.

Whole-genome sequencing in prenatally detected congenital malformations: prospective cohort study in clinical setting.

Objective: To investigate the diagnostic yield of trio whole-genome sequencing (WGS) in fetuses with various congenital malformations referred to a tertiary center for prenatal diagnosis.

Methods: In this prospective study, 50 pregnancies with different congenital malformations, negative for trisomies and causative copy-number variants, were analyzed further with fetal-parental trio WGS analysis. Parents were eligible for inclusion if they accepted further investigation following the detection of isolated or multiple malformations on prenatal ultrasound.

Estimated number of reported vaccine-preventable disease cases averted following the introduction of routine vaccination programs in Sweden, 1910-2019.

Background: Routine childhood vaccination programs have had enormous positive public health impacts worldwide. However, in some areas, these benefits may be impeded by vaccine hesitancy and undervaccination. We estimated the number of reported cases of measles, pertussis, mumps and poliomyelitis averted in Sweden after the introduction of routine childhood vaccination programs.

Break-induced replication underlies formation of inverted triplications and generates unexpected diversity in haplotype structures.

Background: The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a type of complex genomic rearrangement (CGR) hypothesized to result from replicative repair of DNA due to replication fork collapse. It is often mediated by a pair of inverted low-copy repeats (LCR) followed by iterative template switches resulting in at least two breakpoint junctions . Although it has been identified as an important mutation signature of pathogenicity for genomic disorders and cancer genomes, its architecture remains unresolved and is predicted to display at least four structural variation (SV) haplotypes.

Prices of paediatric vaccines in European vaccination programmes.

Objective: To compare the vaccine prices per vaccinated child under 18 and vaccine funding and procurement systems in the national vaccination programmes (NVPs) in Europe.

Methods: The on-line survey targeted to NVP managers collected data referred to the information available on 31 December 2016. The prices of vaccines were categorised into three groups.

Unraveling mucolipidosis type III gamma through whole genome sequencing in late-onset retinitis pigmentosa: a case report.

Background: We describe the case of a 47-year-old man referred to a retinal clinic and diagnosed with late-onset retinitis pigmentosa. Surprisingly, genetic testing revealed compound heterozygous pathogenic variants in GNPTG, leading to the diagnosis of the autosomal recessive lysosomal storage disorder mucolipidosis type III gamma. Mucolipidosis type III gamma is typically diagnosed during childhood due to symptoms relating to skeletal dysplasia.