Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

Challenges to informed consent for exome sequencing: A best-worst scaling experiment.

As exome sequencing expands as a diagnostic tool, patients and providers have voiced concerns about communicating the breadth and scope of potential results when obtaining informed consent. This study aimed to understand how genetic counselors prioritize essential components of the informed consent process and whether counselor factors influence these decisions. Development of a best-worst scaling experiment was informed by a systematic literature review and two focus groups. In all, 11 choice sets were created using a balanced incomplete block design, where participants selected the most and least important object in each set. Mean best-worst (BW) scores were calculated to summarize the relative importance of each object, and mediation analyses assessed whether responses were associated with genetic counselor factors and attitudes. In all, 342 members of the National Society of Genetic Counselors completed the online survey. Ranking of BW scores suggests that participants prioritize collaborative decision-making, assessing understanding and managing expectations, with the least emphasis placed on discussing technological complexities. Stratified analyses found that counselors more experienced with obtaining informed consent for exome sequencing and those reporting higher perceptions of patients' ability to manage information rated discussing variants of uncertain significance as significantly more important (p < .05). Our results suggest that genetic counselors report intentions to prioritize individual patient needs when obtaining informed consent for exome sequencing. Professional characteristics and attitudes may influence preemptive discussion of uncertain results.

Delirium and dementia with Lewy bodies: distinct diagnoses or part of the same spectrum?

Dementia with Lewy bodies (DLB) is recognised as the second most common form of dementia in older people. Delirium is a condition of acute brain dysfunction for which a pre-existing diagnosis of dementia is a risk factor. Conversely delirium is associated with an increased risk of developing dementia. The reasons for this bidirectional relationship are not well understood. Our aim was to review possible similarities in the clinical presentation and pathophysiology between delirium and DLB, and explore possible links between these diagnoses. A systematic search using Medline, Embase and Psychinfo was performed. References were scanned for relevant articles, supplemented by articles identified from reference lists and those known to the authors. 94 articles were selected for inclusion in the review. Delirium and DLB share a number of clinical similarities, including global impairment of cognition, fluctuations in attention and perceptual abnormalities. Delirium is a frequent presenting feature of DLB. In terms of pathophysiological mechanisms, cholinergic dysfunction and genetics may provide a common link. Neuroimaging studies suggest a brain vulnerability in delirium which may also occur in dementia. The basal ganglia, which play a key role in DLB, have also been implicated in delirium. The role of Cerebrospinal fluid (CSF) and serum biomarkers for both diagnoses is an interesting area although some results are conflicting and further work in this area is needed. Delirium and DLB share a number of features and we hypothesise that delirium may, in some cases, represent early or 'prodromal' DLB. Further research is needed to test the novel hypothesis that delirium may be an early marker for future DLB, which would aid early diagnosis of DLB and identify those at high risk.

Identification of a possible respiratory arsenate reductase in Denitrovibrio acetiphilus, a member of the phylum Deferribacteres.

Denitrovibrio acetiphilus N2460(T) is one of the few members of the phylum Deferribacteres with a sequenced genome. N2460(T) was capable of growing with dimethyl sulfoxide, selenate, or arsenate provided as a terminal electron acceptor, and we identified 15 genes that could possibly encode respiratory reductases for these compounds. The protein encoded by one of these genes, YP_003504839, clustered with respiratory arsenate reductases on a phylogenetic tree. Transcription of the gene for YP_003504839, Dacet_2121, was highly induced when arsenate was provided as a terminal electron acceptor. Dacet_2121 exists in a possible operon that is distinct from the previously characterized respiratory arsenate reductase operon in Shewanella sp. ANA-3.

Understanding the phenotypic spectrum and family experiences of XYY syndrome: Important considerations for genetic counseling.

XYY syndrome is characterized by a variable neurodevelopmental phenotype, with features including developmental delays, cognitive impairments, and an increased risk for mental health conditions. There are two recent developments that have primarily motivated this review. The first is the increased use of non-invasive prenatal screening (NIPS), which will likely result in more individuals being diagnosed with XYY prenatally. As such, health care providers (HCPs) both within genetics and outside of the specialty are more likely to encounter this diagnosis in the future. The second is advances in the understanding of the phenotypic variability of XYY through biobank and deep phenotyping efforts. As the phenotypic spectrum of XYY syndrome continues to expand, families will face greater uncertainty when receiving this diagnosis. Given both of these developments, HCPs will need to have up-to-date and accurate information about XYY to better counsel families. Furthermore, the ability to employ effective counseling techniques, such as anticipatory guidance, will aid in supporting and guiding families through the diagnostic journey. This review aims to provide insight on the neurodevelopmental and psychosocial aspects of XYY syndrome by discussing current research and borrowing from the relevant psychosocial literature of other genetic conditions. In this way, we hope to equip HCPs with the ultimate goal of improving the care and support provided to individuals with XYY and their families.

Duplication 6q24: More Than Just Diabetes.

Chromosome 6q24-related transient neonatal diabetes mellitus is characterized by intrauterine growth restriction and low birth weight, with neonatal hyperglycemia resolving by 18 months and an increased risk for type 2 diabetes in adulthood. Molecularly, it is caused by overexpression of the 6q24 imprinted chromosomal region due to a duplication, uniparental disomy, or abnormal methylation. Conventional testing for this condition analyzes methylation patterns at the 6q24 locus but does not evaluate for the presence of other surrounding chromosomal abnormalities. We report a female with a history of neonatal hyperglycemia due to a paternally inherited duplication at chromosomal location 6q24. She subsequently presented to the pediatric genetics clinic at 15 months of age with developmental delay and abnormal balance. Microarray analysis identified a larger 14 Mb chromosomal duplication from 6q24 to 6q25.2, consistent with a diagnosis of duplication 6q syndrome. This case highlights the clinical importance of pursuing further genetic evaluation in patients diagnosed with chromosome 6q24-related neonatal hyperglycemia via targeted methylation-specific multiplex ligation-dependent probe amplification analysis identifying a duplication in this region. Early identification and intervention can improve developmental outcomes for patients with larger chromosome 6q duplications.