Heating up three cold cases in Norway using investigative genetic genealogy.

With the advent of commercial DNA databases, investigative genetic genealogy (IGG) has emerged as a powerful forensic tool, rivalling the impact of STR analyses, introduced four decades ago. IGG has been frequently applied in the US and tested in other countries, but never in Norway. Here, we apply IGG to three cold criminal cases and successfully identify the donor of the DNA in two of these cases.

shinyseg: a web application for flexible cosegregation and sensitivity analysis.

Motivation: Cosegregation analysis is a powerful tool for identifying pathogenic genetic variants, but its implementation remains challenging. Existing software is either limited in scope or too demanding for many end users. Moreover, current solutions lack methods for assessing the robustness of cosegregation evidence, which is important due to its reliance on uncertain estimates.

A 39 kb structural variant causing Lynch Syndrome detected by optical genome mapping and nanopore sequencing.

Lynch Syndrome (LS) is a hereditary cancer syndrome caused by pathogenic germline variants in one of the four mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. It is characterized by a significantly increased risk of multiple cancer types, particularly colorectal and endometrial cancer, with autosomal dominant inheritance. Access to precise and sensitive methods for genetic testing is important, as early detection and prevention of cancer is possible when the variant is known.

The invisible witness: air and dust as DNA evidence of human occupancy in indoor premises.

Humans constantly shed deoxyribonucleic acid (DNA) into the surrounding environment. This DNA may either remain suspended in the air or it settles onto surfaces as indoor dust. In this study, we explored the potential use of human DNA recovered from air and dust to investigate crimes where there are no visible traces available-for example, from a recently vacated drugs factory where multiple workers had been present.

Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes.

Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients ( = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study.

Two-locus identity coefficients in pedigrees.

This paper proposes a solution to a long-standing problem concerning the joint distribution of allelic identity by descent between two individuals at two linked loci. Such distributions have important applications across various fields of genetics, and detailed formulas for selected relationships appear scattered throughout the literature. However, these results were obtained essentially by brute force, with no efficient method available for general pedigrees.

The use of segregation analysis in interpretation of sequence variants in SMAD3: A case report.

Background: While representing a significant improvement, the introduction of next-generation sequencing in genetic diagnosis also prompted new challenges. Despite widely recognized consensus guidelines for the interpretation of sequence variants, many variants remain unclassified or are discordantly interpreted. In heritable thoracic aortic aneurysms with dissection (HTAAD), most cases are caused by a heterozygous, private missense mutation, possibly contributing to the relatively common reports of variants with uncertain significance in this group.

QuickPed: an online tool for drawing pedigrees and analysing relatedness.

Background: The ubiquity of pedigrees in many scientific areas calls for versatile and user-friendly software. Previously published online pedigree tools have limited support for complex pedigrees and do not provide analysis of relatedness between pedigree members.

Results: We introduce QuickPed, a web application for interactive pedigree creation and analysis.

Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in .

The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets.

Whole-exome sequencing in syndromic craniosynostosis increases diagnostic yield and identifies candidate genes in osteogenic signaling pathways.

Craniosynostosis (CS) is a common congenital anomaly defined by premature fusion of one or more cranial sutures. Syndromic CS involves additional organ anomalies or neurocognitive deficits and accounts for 25%-30% of the cases. In a recent population-based study by our group, 84% of the syndromic CS cases had a genetically verified diagnosis after targeted analyses.

Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement.

Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood.

Joint DNA-based disaster victim identification.

We address computational and statistical aspects of DNA-based identification of victims in the aftermath of disasters. Current methods and software for such identification typically consider each victim individually, leading to suboptimal power of identification and potential inconsistencies in the statistical summary of the evidence. We resolve these problems by performing joint identification of all victims, using the complete genetic data set.

Making decisions in missing person identification cases with low statistical power.

The present work proposes a general strategy for dealing with missing person identification cases through DNA-database search. Our main example is the identification of abducted children in the last civic-dictatorship of Argentina, known as the "Missing Grandchildren of Argentina". Particularly we focus on those pedigrees where few, or only distant relatives of the missing person are available, resulting in low statistical power.

A novel somatic mutation in GNB2 provides new insights to the pathogenesis of Sturge-Weber syndrome.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations affecting skin, eyes and leptomeninges of the brain, which can lead to glaucoma, seizures and intellectual disability. The discovery of a disease-causing somatic missense mutation in the GNAQ gene, encoding an alpha chain of heterotrimeric G-proteins, has initiated efforts to understand how G-proteins contribute to SWS pathogenesis. The mutation is predominantly detected in endothelial cells and is currently believed to affect downstream MAPK signalling.

Differential Glial Activation in Early Epileptogenesis-Insights From Cell-Specific Analysis of DNA Methylation and Gene Expression in the Contralateral Hippocampus.

Morphological changes in mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) are well-characterized. Yet, it remains elusive whether these are a consequence of seizures or originate from a hitherto unknown underlying pathology. We recently published data on changes in gene expression and DNA methylation in the ipsilateral hippocampus (ILH) using the intracortical kainate mouse model of mTLE-HS.

Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis.

An accurate diagnosis of syndromic craniosynostosis (CS) is important for personalized treatment, surveillance, and genetic counselling. We describe detailed clinical criteria for syndromic CS and the distribution of genetic diagnoses within the cohort. The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve individuals with syndromic CS born between 1 January 2002 and 30 June 2019.

Elevated hydroxycholesterols in Norwegian patients with hereditary spastic paraplegia SPG5.

Spastic paraplegia type 5 (SPG5/HSP-CYP7B1) is an autosomal recessive hereditary spastic paraplegia (HSP) caused by biallelic variants in the CYP7B1 gene, resulting in dysfunction of the enzyme oxysterol-7-α-hydroxylase. The consequent accumulation of hydroxycholesterols in plasma seems to be pathognomonic for SPG5, and represent a possible target for treatment. We aimed to characterize Norwegian patients with SPG5, including clinical examinations, genetic analyses, measurements of hydroxycholesterols, electrophysiological investigations and brain imaging.

Pairwise relatedness testing in the context of inbreeding: expectation and variance of the likelihood ratio.

In this paper we investigate various effects of inbreeding on the likelihood ratio (LR) in forensic kinship testing. The basic setup of such testing involves formulating two competing hypotheses, in the form of pedigrees, describing the relationship between the individuals. The likelihood of each hypothesis is computed given the available genetic data, and a conclusion is reached if the ratio of these exceeds some pre-determined threshold.

Prioritising family members for genotyping in missing person cases: A general approach combining the statistical power of exclusion and inclusion.

Missing person identification typically involves genetic matching of a person of interest against relatives of the missing person. In cases with few available relatives, exhumations or other substantial efforts may be necessary in order to secure adequate statistical power. We propose a simulation approach for solving prioritisation problems arising in such cases.

Relatedness coefficients in pedigrees with inbred founders.

We study an extension of the standard framework for pedigree analysis, in which we allow pedigree founders to be inbred. This solves a number of practical challenges in calculating coefficients of relatedness, including condensed identity coefficients. As a consequence we expand considerably the class of pedigrees for which such coefficients may be efficiently computed.

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.

Purpose: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.

Methods: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers.

Mitochondrial genome-wide association study of migraine - the HUNT Study.

Background: Variation in mitochondrial DNA (mtDNA) has been indicated in migraine pathogenesis, but genetic studies to date have focused on candidate variants, with sparse findings. We aimed to perform the first mitochondrial genome-wide association study of migraine, examining both single variants and mitochondrial haplogroups.

Methods: In total, 71,860 participants from the population-based Nord-Trøndelag Health Study were genotyped.