Novel characterization of CASK variant c.1963 A>G (p.Asn655Asp) through whole-exome sequencing in a monochorionic diamniotic twin fetus with significant brain anomalies: A case report.

Whole-exome sequencing is an evolving technology in perinatal diagnosis which allows identification of genetic etiologies that would otherwise go undetermined. In this case report, a 38-year-old Hispanic woman, G5P3013, with a monochorionic diamniotic twin gestation with one fetus displaying significant cranial abnormalities on prenatal ultrasound and magnetic resonance imaging (MRI) of the brain is presented. Fetal anomalies included bilateral ventriculomegaly, absent cavum septum pellucidum, and absent corpus callosum. Diagnostic amniocentesis with chromosome analysis, chromosomal microarray, alpha-fetoprotein, cytomegalovirus, toxoplasmosis, and parvovirus had normal results. Whole-exome sequencing for the anomalous fetus detected a de novo mosaic variant of uncertain significance (VUS) in the calcium/calmodulin dependent serine protein kinase (CASK) gene: c.1963 A > G (p.Asn655Asp). This variant was absent in the normal twin fetus, the mother, and the father. Pathogenic CASK gene mutations are associated with three syndromes: FG syndrome 4, intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH), and intellectual developmental disorder with or without nystagmus. Whole-exome sequencing identified a potential etiology for the anomalies detected. The variant likely arose de novo and was the potential cause of the identified cranial abnormalities in one fetus of this monochorionic diamniotic twin gestation. Whole-exome sequencing may provide additional diagnostic utility when standard diagnostic testing is noncontributory.

"Knowledge is Power": Parent Views on the Benefits of Early Diagnosis and Awareness of Sex Chromosome Multisomy Among Pediatric Professionals.

OBJECTIVE: Pediatric diagnoses of sex chromosome multisomies (SCMs) have increased as genetic testing has expanded. However, depending on SCM presentation, there may be significant delays between symptom recognition and diagnosis. We conducted a survey of parents of children diagnosed with SCMs to understand their experiences receiving an SCM diagnosis and their support needs. METHODS: We conducted an inductive qualitative analysis of open-ended survey responses for iterative themes related to presenting symptoms, diagnostic odyssey, immediate and long-term support needs, and awareness of SCMs. RESULTS: Of the 323 parents who completed the survey, 185 parents received a pediatric diagnosis (0-21 years) in a child. Many parents expressed feelings of relief when receiving the diagnosis, especially if it occurred after a lengthy diagnostic odyssey. Parents reported frustration that their child's nonmedical symptoms, including learning disabilities, speech delays, attention deficits, and behavioral issues, were not flagged as potential indications for SCMs and suggested that greater awareness of SCMs by pediatricians, educators, and other professionals involved in their child's care may lead to earlier diagnosis and intervention. CONCLUSION: This is the largest qualitative study to date examining parent and caregiver experiences with a pediatric diagnosis of SCMs. Increased knowledge and awareness of nonmedical SCM symptoms are needed among medical, education, occupational, and psychology professionals for early testing referral and improved support of children with SCMs.

Motivations for concurrent use of uppers and downers among people who access harm reduction services in British Columbia, Canada: findings from the 2019 Harm Reduction Client Survey.

INTRODUCTION: An increase in crystal methamphetamine (methamphetamine) use during the overdose epidemic is being observed in British Columbia (BC), Canada, and across North America. Concurrent use (ie, using uppers and downers one after the other or together) can increase the risk of fatal and non-fatal opioid overdose. OBJECTIVES: We investigated motivations for concurrent use of uppers and downers, specifically how (eg, in what order) and why people use concurrently, to identify potential interventions to prevent overdose and other harms. SETTING AND PARTICIPANTS: The 2019 Harm Reduction Client Survey was administered across 22 harm reduction supply distribution sites in BC (n=621). This thematic analysis examined 307 responses by people who affirmed concurrent use to classify order and reasons for using uppers and downers concurrently. RESULTS: Of the 307 people who responded 'yes' to concurrent use, 179 (58.3%) used downers then uppers, 76 (24.8%) used uppers then downers and 184 (59.9%) mixed uppers and downers together. Four main reasons for concurrent use emerged: self-medication, availability and preference, drug effects/properties, and financial and life situation. People who mixed drugs together predominantly wanted to achieve desired drug effects/properties, such as a specific high or balancing stimulating and sedating effects. CONCLUSIONS: The ongoing rise in overdoses in BC is multifactorial, and the recent parallel increases in methamphetamine use and concurrent use with opioids may contribute. Qualitative interviews may further elucidate reasons for concurrent use. Addressing reasons for concurrent use identified in this study through harm reduction strategies and education may affect the rates of overdose morbidity and mortality.

Correlates of concurrent use of stimulants and opioids among people who access harm reduction services in British Columbia, Canada: Findings from the 2019 Harm Reduction Client Survey.

BACKGROUND: During a public health overdose emergency driven by fentanyl in British Columbia (BC), Canada, a parallel increase in concurrent use of methamphetamines may be contributing to the risk of overdose. Concurrent use refers to the use of stimulants and opioids one after the other, or together. Describing substance use practices and elucidating correlates of concurrent use can inform harm reduction service provision and prevent overdose events. METHODS: This cross-sectional study analyzed the 2019 Harm Reduction Client Survey administered at 22 harm reduction sites across BC and sampled individuals aged 19 and older. Bivariable and multivariable logistic regression models identified correlates of concurrent use of stimulants and opioids in the last three days. RESULTS: The study sample was composed of 574 individuals who used stimulants and/or opioids, among whom 307 (53.5%) reported concurrent use. Compared with individuals who used stimulants and/or opioids separately, the odds of concurrent use were significantly increased (OR=2.74, 95%CI 1.71-4.51) while the adjusted odds were increased (aOR=1.79, 95%CI 0.98-3.34) among individuals who experienced an opioid overdose. Further, the adjusted odds of concurrent use decreased with every one-year increase in age (aOR=0.97, 95%CI 0.95-0.99), among individuals with paid work (aOR=0.58, 95%CI 0.33-0.99), and stable housing (aOR=0.61, 95%CI 0.37-1.02). The adjusted odds of concurrent use increased among individuals who used drugs daily (aOR=3.78, 95%CI 2.28-6.40), used tobacco (aOR=2.03, 95%CI 1.09-3.87), used benzodiazepines (aOR=3.72, 95%CI 1.76-8.41), owned a naloxone kit (aOR=1.94, 95%CI 1.15-3.31), used observed consumption sites (aOR=2.51, 95%CI 1.57-4.07), and were prescribed opioid agonist therapy (aOR=2.92, 95%CI 1.81-4.77). CONCLUSIONS: Individuals who used stimulants and opioids concurrently tend to be younger, without paid work or housing. They were engaged in harm reduction and treatment services, yet used illicit drugs with unknown concentration daily. Improving access to age-appropriate services and expanding the availability of both legal and regulated stimulants and opioids may further reduce harms of concurrent use.