A Haplotype GWAS in Syndromic Familial Colorectal Cancer.

A previous genome-wide association study (GWAS) in colorectal cancer (CRC) patients with gastric and/or prostate cancer in their families suggested genetic loci with a shared risk for these three cancers. A second haplotype GWAS was undertaken in the same colorectal cancer patients and different controls with the aim of confirming the result and finding novel loci. The haplotype GWAS analysis involved 685 patients with colorectal cancer cases and 1642 healthy controls from Sweden.

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).

Detection of clinically relevant variants in the gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL.

In chronic lymphocytic leukemia, the reliability of next-generation sequencing (NGS) to detect variants ≤10% allelic frequency (low-VAF) is debated. We tested the ability to detect 23 such variants in 41 different laboratories using their NGS method of choice. The sensitivity was 85.

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.

An X-Linked Ataxia Syndrome in a Family with Hearing Loss Associated with a Novel Variant in the BCAP31 Gene.

Objective: Pathogenic variants in B-cell receptor-associated protein (BCAP31) are associated with X-linked, deafness, dystonia and cerebral hypomyelination (DDCH) syndrome. DDCH is congenital and non-progressive, featuring severe intellectual disability (ID), variable dysmorphism, and sometimes associated with shortened survival. BCAP31 encodes one of the most abundant chaperones, with several functions including acting as a negative regulator of endoplasmic reticulum (ER) calcium ion (Ca) concentration.

A GWAS Suggesting Genetic Modifiers to Increase the Risk of Colorectal Cancer from Antibiotic Use.

Background: Antibiotics have recently been suggested to increase the risk of colorectal cancer. Here, we aimed to investigate the association of frequent antibiotic use and genetic susceptibility with the increased risk of the development of colorectal cancer. Therefore, a genome-wide association study was conducted in colorectal cancer patients with frequent antibiotic use and controls to identify potential chromosomal regions that could indicate an increased risk of colorectal cancer associated with antibiotic use.

Anti-gene oligonucleotide clamps invade dsDNA and downregulate expression.

Anti-gene oligonucleotides belong to a group of therapeutic compounds, which, in contrast to antisense oligonucleotides, bind to DNA. Clamp anti-gene oligonucleotides bind through a double-stranded invasion mechanism. With two arms connected by a linker, they hybridize to one of the DNA strands forming Watson-Crick and Hoogsteen hydrogen bonds.

Characterisation of heritable TP53-related cancer syndrome in Sweden-a nationwide study of genotype-phenotype correlations in 90 families.

We aimed to describe the clinical characteristics of families with heritable TP53-related cancer (hTP53rc) syndrome in Sweden with class 4 and 5 germline TP53 variants (gTP53), and to evaluate the genotype-phenotype correlation. These results were also used to evaluate our previously published phenotype prediction model based on TP53 missense variants and their impact on protein conformation. 90 families with hTP53rc were initially identified in Sweden.

Differential regulatory effects of the N-terminal region in SYK-fusion kinases reveal unique activation-inducible nuclear translocation of ITK-SYK.

ITK-SYK and TEL-SYK (also known as ETV6-SYK) are human tumor-causing chimeric proteins containing the kinase region of SYK, and the membrane-targeting, N-terminal, PH-TH domain-doublet of ITK or the dimerizing SAM-PNT domain of TEL, respectively. ITK-SYK causes peripheral T cell lymphoma, while TEL-SYK was reported in myelodysplastic syndrome. BTK is a kinase highly related to ITK and to further delineate the role of the N-terminus, we generated the corresponding fusion-kinase BTK-SYK.

Integration of personalised ultrasensitive ctDNA monitoring of patients with metastatic breast cancer to reduce imaging requirements.

Circulating tumour DNA (ctDNA) is an emerging biomarker for monitoring cancers. The personalised disease monitoring in metastatic breast cancer (PDM-MBC) study is an ongoing study instigated to evaluate ctDNA as a biomarker to individualise imaging requirements in patients with MBC. Patients receiving first-line endocrine therapy (aromatase inhibitor + cyclin-dependent kinase 4/6 inhibitor) had plasma samples collected pre-treatment, weeks 2 and 4, and concurrently with imaging until progressive disease (PD).

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.

Candidate Genetic Loci Modifying the Colorectal Cancer Risk Caused by Lifestyle Risk Factors.

Introduction: 65%-70% of colorectal cancer (CRC) cases are considered sporadic; they arise under the influence of environmental factors in individuals lacking a family history of CRC. Low-risk genetic variants are believed to contribute to CRC risk, in tandem with lifestyle factors.

Methods: Six hundred sixteen nonfamilial Swedish CRC cases with at least 1 of the following 5 risk factors: smoking, excessive alcohol consumption, physical inactivity, adherence to an unhealthy diet, and excess body weight were included in this study.

Diagnostic and prognostic genomic aberrations in upper tract urothelial carcinoma can be identified in focal barbotage samples.

Objectives: To investigate whether genetic analysis of focal barbotage samples obtained at ureterorenoscopy (URS) is possible, and to identify genetic aberrations that might add prognostic information.

Methods: This prospective study included barbotage samples from 42 patients with upper urinary tract urothelial carcinoma (UTUC) confirmed at URS. At URS, focal barbotage specimens were collected for cytology and for gene sequencing.

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).

Plasma brain-derived tau correlates with cerebral infarct volume.

Background: A blood-based biomarker that accurately reflects neuronal injury in acute ischemic stroke could be an easily accessible and cost-effective complement to clinical and radiological evaluation. Here, we investigate whether plasma levels of the novel biomarker brain-derived tau (BD-tau) reflect cerebral infarct volumes and whether BD-tau can improve clinical outcome prediction.

Methods: The present study included 713 consecutive cases from two different hospital-based cohorts, the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) and SAHLSIS phase 2 (SAHLSIS2).

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.

Unclassifiable short-rib thoracic dysplasia diagnosed using targeted gene panel sequencing.

We report a case of a fetus with short-rib thoracic dysplasia (SRTD) with polydactyly that also presented with atypical severe acro-mesomelic ossification defects. Genetic analysis using massively parallel sequencing of a skeletal dysplasia panel revealed compound heterozygous variants in DYNC2H1. This clinical report highlights the challenges associated with diagnosing the diverse phenotypes in the SRTD group and emphasizes the importance of genetic surveillance with a targeted gene panel for accurate diagnosis.

Identification of biallelic POLA2 variants in two families with an autosomal recessive telomere biology disorder.

POLA2 encodes the accessory subunit of DNA polymerase α (polα)/primase, which is crucial for telomere C-strand fill-in. Incomplete fill-in of the C-rich telomeric strand after DNA replication has been proposed as a mechanism for Coats plus syndrome, a phenotype within the broader spectrum of telomere biology disorders (TBD). Coats plus syndrome has so far been associated with pathogenic variants in POT1, CTC1, and STN1.

Personalized circulating tumor DNA analysis for sensitive disease monitoring and detection of relapse in neuroblastoma.

Circulating tumor DNA (ctDNA) has shown potential as a non-invasive tumor biomarker in neuroblastoma. Previous studies used generic assays for detection of selected predefined oncogenic variants as markers of ctDNA, which limits the sensitivity and excludes a subset of patients from analysis. Here we assessed patient-specific ctDNA analysis for treatment evaluation and detection of relapse in neuroblastoma.

Detecting transposable elements in long-read genomes using sTELLeR.

Motivation: Repeat elements, such as transposable elements (TE), are highly repetitive DNA sequences that compose around 50% of the genome. TEs such as Alu, SVA, HERV, and L1 elements can cause disease through disrupting genes, causing frameshift mutations or altering splicing patters. These are elements challenging to characterize using short-read genome sequencing, due to its read length and TEs repetitive nature.

Mechanistic basis of atypical TERT promoter mutations.

Non-coding mutations in the TERT promoter (TERTp), typically at one of two bases -124 and -146 bp upstream of the start codon, are among the most prevalent driver mutations in human cancer. Several additional recurrent TERTp mutations have been reported but their functions and origins remain largely unexplained. Here, we show that atypical TERTp mutations arise secondary to canonical TERTp mutations in a two-step process.

VizCNV: An integrated platform for concurrent phased BAF and CNV analysis with trio genome sequencing data.

Background: Copy number variation (CNV) is a class of genomic Structural Variation (SV) that underlie genomic disorders and can have profound implications for health. Short-read genome sequencing (sr-GS) enables CNV calling for genomic intervals of variable size and across multiple phenotypes. However, unresolved challenges include an overwhelming number of false-positive calls due to systematic biases from non-uniform read coverage and collapsed calls resulting from the abundance of paralogous segments and repetitive elements in the human genome.

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.