StarPhase: Comprehensive Phase-Aware Pharmacogenomic Diplotyper for Long-Read Sequencing Data.

Pharmacogenomics is central to precision medicine, informing medication safety and efficacy. Pharmacogenomic diplotyping of complex genes requires full-length DNA sequences and detection of structural rearrangements. We introduce StarPhase, a tool that leverages PacBio HiFi sequence data to diplotype 21 CPIC Level A pharmacogenes and provides detailed haplotypes and supporting visualizations for , , and .

Allele-specific transcription factor binding across human brain regions offers mechanistic insight into eQTLs.

Transcription factors (TFs) regulate gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Because TF occupancy is driven in part by recognition of DNA sequence, genetic variation can influence TF-DNA associations and gene regulation. To identify variants that impact TF binding in human brain tissues, we assessed allele-specific binding (ASB) at heterozygous variants for 94 TFs in nine brain regions from two donors.

Allele biased transcription factor binding across human brain regions gives mechanistic insight into eQTLs.

Transcription Factors (TFs) influence gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Because genomic localization of TFs is in part driven by TF recognition of DNA sequence, variation in TF binding sites can disrupt TF-DNA associations and affect gene regulation. To identify variants that impact TF binding in human brain tissues, we quantified allele bias for 93 TFs analyzed with ChIP-seq experiments of multiple structural brain regions from two donors.

Contributions of rare and common variation to early-onset and atypical dementia risk.

We collected and analyzed genomic sequencing data from individuals with clinician- diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with sixty-eight newly described in this report. Of those sixty-eight, sixty-two patients reported Caucasian, non-Hispanic ethnicity and six reported as African American, non-Hispanic.

Lessons learned and recommendations for data coordination in collaborative research: The CSER consortium experience.

Integrating data across heterogeneous research environments is a key challenge in multi-site, collaborative research projects. While it is important to allow for natural variation in data collection protocols across research sites, it is also important to achieve interoperability between datasets in order to reap the full benefits of collaborative work. However, there are few standards to guide the data coordination process from project conception to completion.

Coming Full Circle: Reflections and Inspirations from a Cystic Fibrosis Patient Scientist Panel.

Care for many progressive chronic diseases continues to improve, allowing patients to survive and thrive for longer periods of time. People living with such conditions may now find themselves able to achieve long-term goals in education and career development. Many people now occupy the dual roles of scientist and patient.

Patient and family experience of telehealth care delivery as part of the CF chronic care model early in the COVID-19 pandemic.

Background: During the COVID-19 pandemic, CF centers shifted to a telehealth delivery model. Our study aimed to determine how people with CF (PwCF) and their families experienced telehealth and assessed its quality and acceptability for future CF care.

Methods: The CF Patient and Family State of Care Survey (PFSoC) was fielded from August 31-October 30, 2020.

Long-read genome sequencing for the molecular diagnosis of neurodevelopmental disorders.

Exome and genome sequencing have proven to be effective tools for the diagnosis of neurodevelopmental disorders (NDDs), but large fractions of NDDs cannot be attributed to currently detectable genetic variation. This is likely, at least in part, a result of the fact that many genetic variants are difficult or impossible to detect through typical short-read sequencing approaches. Here, we describe a genomic analysis using Pacific Biosciences circular consensus sequencing (CCS) reads, which are both long (>10 kb) and accurate (>99% bp accuracy).

The Therapeutic Odyssey: Positioning Genomic Sequencing in the Search for a Child's Best Possible Life.

The desire of parents to obtain a genetic diagnosis for their child with intellectual disability and associated symptoms has long been framed as a diagnostic odyssey, an arduous and sometimes perilous journey focused on the goal of identifying a cause for the child's condition. Semi-structured interviews (N = 60) were conducted with parents of children (N = 59, aged 2-24 years) with intellectual disability and/or developmental delay (IDD) who underwent genome sequencing at a single pediatric multispecialty clinic. Interviews were conducted after parents received their child's sequencing result (positive findings, negative findings, or variants of unknown significance).

Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls.

Purpose: To evaluate the effectiveness and specificity of population-based genomic screening in Alabama.

Methods: The Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results.

Results: Among 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP).

Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis.

Cystic Fibrosis (CF) is caused most often by removal of amino acid 508 (Phe508del, deltaF508) within CFTR, yet dozens of additional CFTR variants are known to give rise to CF and many variants in the genome are known to contribute to CF pathology. To address CFTR coding variants, we developed a sequence-to-structure-to-dynamic matrix for all amino acids of CFTR using 233 vertebrate species, CFTR structure within a lipid membrane, and 20 ns of molecular dynamic simulation to assess known variants from the CFTR1, CFTR2, ClinVar, TOPmed, gnomAD, and COSMIC databases. Surprisingly, we identify 18 variants of uncertain significance within CFTR from diverse populations that are heritable and a likely cause of CF that have been understudied due to nonexistence in Caucasian populations.

Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles.

We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with repeat expansion testing.

Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder.

Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge.

Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies.

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs. This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES).

Genomic sequencing identifies secondary findings in a cohort of parent study participants.

Purpose: Clinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability.

Methods: Exome/genome sequencing and analysis of 789 "unaffected" parents was performed.

Results: Pathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.

The influence of Gaussian strain on sublattice selectivity of impurities in graphene.

Among the different strategies used to induce the opening of a band gap in graphene, one common practice is through chemical doping. While a gap may be opened in this way, disorder-induced scattering is an unwanted side-effect that impacts the electron mobility in the conductive regime of the system. However, this undesirable side effect is known to be minimised if dopants interact asymmetrically with the two sublattices of graphene.

Sublattice asymmetry of impurity doping in graphene: A review.

In this review we highlight recent theoretical and experimental work on sublattice asymmetric doping of impurities in graphene, with a focus on substitutional nitrogen dopants. It is well known that one current limitation of graphene in regards to its use in electronics is that in its ordinary state it exhibits no band gap. By doping one of its two sublattices preferentially it is possible to not only open such a gap, which can furthermore be tuned through control of the dopant concentration, but in theory produce quasi-ballistic transport of electrons in the undoped sublattice, both important qualities for any graphene device to be used competetively in future technology.