All-cause mortality and survival in adults with 22q11.2 deletion syndrome.

PURPOSE: Given limited data available on long-term outcomes in 22q11.2 deletion syndrome (22q11.2DS), we investigated mortality risk in adults with this microdeletion syndrome. METHODS: We studied 309 well-characterized adults (age ≥17 years) with 22q11.2DS and their 1014 unaffected parents and siblings, using a prospective case-control design. We used Cox proportional hazards regression modeling and Kaplan-Meier curves to investigate effects of the 22q11.2 deletion and its associated features on all-cause mortality and survival. RESULTS: The 22q11.2 deletion (hazard ratio [HR] 8.86, 95% CI 2.87-27.37) and major congenital heart disease (CHD; HR 5.03, 95% CI 2.27-11.17), but not intellectual disability or psychotic illness, were significant independent predictors of mortality for adults with 22q11.2DS compared with their siblings. Amongst those with 22q11.2DS, there were 31 deaths that occurred at a median age of 46.4 (range 18.1-68.6) years; a substantial minority had outlived both parents. Probability of survival to age 45 years was approximately 72% for those with major CHD, and 95% for those with no major CHD (p < 0.0001). CONCLUSION: For adults with 22q11.2DS, the 22q11.2 deletion and more severe forms of CHD both contribute to a lower life expectancy than family-based expectations. The results have implications for genetic counseling and anticipatory care.

Fetal growth and gestational factors as predictors of schizophrenia in 22q11.2 deletion syndrome.

PURPOSE: Schizophrenia occurs in 20-25% of adults with 22q11.2 deletion syndrome (22q11.2DS). General population studies of schizophrenia report associations with perinatal complications, although effect sizes are generally low. We aimed to determine whether such factors are associated with expression of schizophrenia in individuals with 22q11.2DS. METHODS: We investigated the relationship of small for gestational age (SGA) birth weight (<3rd percentile for sex and gestational age) and prematurity (<37 weeks gestation) to expression of schizophrenia in a well-characterized cohort of 123 adults with 22q11.2DS. Outcome measures included adjusted odds ratios and positive and negative predictive values (PPV and NPV) for schizophrenia. RESULTS: SGA birth weight (OR = 3.52, 95% CI = 1.34-9.22) and prematurity (OR = 5.38, 95% CI = 1.63-17.75), but not maternal factors, were significant risk factors for schizophrenia in 22q11.2DS. Being born SGA or premature resulted in a PPV of 46% for schizophrenia; NPV in the absence of both features was 83%. Post hoc analyses suggested these perinatal complications were also associated with factors indicative of increased severity of schizophrenia. CONCLUSION: In 22q11.2DS, fetal growth and gestation may have a clinically significant impact on future risk for schizophrenia. These data advance our understanding of determinants of disease-specific expression in 22q11.2DS, with implications for other genomic disorders.Genet Med 18 4, 350-355.

22q11.2 microdeletion and increased risk for type 2 diabetes.

BACKGROUND: The 22q11.2 microdeletion is the pathogenic copy number variation (CNV) associated with 22q11.2 deletion syndrome (22q11.2DS, formerly known as DiGeorge syndrome). Familiar endocrinological manifestations include hypoparathyroidism and hypothyroidism, with recent elucidation of elevated risk for obesity in adults. In this study, we aimed to determine whether adults with 22q11.2DS have an increased risk of developing type 2 diabetes (T2D). METHODS: We studied the effect of the 22q11.2 microdeletion on risk for T2D, defined by history and glycosylated hemoglobin (HbA1c), using weighted survey data from the adult Canadian population (based on n = 11,874) and from a clinical cohort of adults with 22q11.2DS (n = 314), aged 17-69 years. Binomial logistic regression models accounted for age, sex, non-European ethnicity, family history of T2D, obesity, and antipsychotic medication use. FINDINGS: The 22q11.2 microdeletion was a significant independent risk factor for T2D (OR 2·44, 95% CI 1·39-4·31), accounting for other factors (p < 0·0001). All factors except sex were also significant within 22q11.2DS. The median age at diagnosis of T2D was significantly younger in 22q11.2DS than in the Canadian population sample (32 vs 50 years, p < 0·0001). In adults without T2D, HbA1c was significantly higher in 22q11.2DS than the population (p = 0·042), after accounting for younger age of the 22q11.2DS group. INTERPRETATION: The results support the 22q11.2 microdeletion as a novel independent risk factor and potential model for early onset T2D. The findings complement emerging evidence that rare CNVs may contribute to risk for T2D. The results have implications for precision medicine and research into the underlying pathogenesis of T2D.

Impact of a 22q11.2 Microdeletion on Adult All-Cause Mortality in Tetralogy of Fallot Patients.

BACKGROUND: Because of the importance of identifying factors that affect late outcomes in the increasing population of those with tetralogy of Fallot (TOF), we aimed to determine the effect of a 22q11.2 microdeletion on adult mortality, while accounting for pulmonary atresia, known to be enriched in 22q11.2 deletion syndrome (22q11.2DS). METHODS: We studied 612 individuals with TOF recruited as adults at a single centre, 80 (13.1%) with molecularly confirmed 22q11.2 deletions and 532 without 22q11.2DS, followed for a total of 5961.3 person-years. Using a case-control design, Cox proportional hazard regression and Kaplan-Meier curves, we evaluated the effect of a 22q11.2 deletion on mortality and survival. RESULTS: All-cause mortality was 1.87% per person-year in the 22q11.2DS-TOF group and 0.80% in the other-TOF group. The presence of a 22q11.2 microdeletion was a significant predictor of adult mortality in TOF (hazard ratio, 5.00; P < 0.0001), after accounting for pulmonary atresia (hazard ratio, 2.71; P = 0.0106) and other factors. Overall, individuals with 22q11.2DS died on average 17.7 years earlier (P = 0.0055) than others with TOF, predominantly of cardiovascular causes, with proportionately more sudden cardiac deaths in those with 22q11.2DS-TOF (n = 5 [38.5%] vs n = 5 [11.9%], other-TOF; P = 0.0447). Kaplan-Meier curves showed reduced survival for those with 22q11.2DS (P < 0.0001); probability of survival to age 45 years, without pulmonary atresia, was 72% (22q11.2DS-TOF) and 98% (other-TOF). CONCLUSIONS: The results suggest that the 22q11.2 deletion significantly contributes to premature mortality in adults with TOF, mediated only in part by greater anatomic complexity. The interpretation of late outcome data in TOF will likely benefit from further genetic subtyping.

Exploring Receipt of HIV PEP Counseling Among Women Sexually Assaulted by an Intimate Partner.

Among 136 women sexually assaulted by a current or former male intimate partner presenting to hospital-based violence treatment centers, 58 (42.6%) received HIV post-exposure prophylaxis (HIV PEP) counseling by a specially trained sexual assault nurse. We identified factors that were associated with receipt of HIV PEP counseling. Those who received counseling were more likely to have been younger than 25 years of age, single, a student, vaginally penetrated, and have received various other services (e.g., STI prophylaxis). They were less likely to have been unemployed. Hospital-based violence treatment centers need to be aware that not all women sexually assaulted by an intimate partner will have the same risk of acquisition of HIV and care needs.

Update on the 22q11.2 deletion syndrome and its relevance to schizophrenia.

PURPOSE OF REVIEW: Schizophrenia occurs in ∼25% of individuals with 22q11.2 deletion syndrome (22q11.2DS), the strongest known molecular genetic risk factor for schizophrenia. This review highlights recent literature in 22q11.2DS as it pertains to psychosis and schizophrenia. RECENT FINDINGS: Advances in noninvasive prenatal testing allow for early detection of 22q11.2DS in utero, whereas premature birth has been shown to be a significant risk factor for development of psychotic illness in 22q11.2DS. Impairments in various domains of cognitive and social functioning, as well as neuroanatomical alterations, are comparable with those in other high-risk groups and may serve as early signs of psychosis in 22q11.2DS. Novel research on the pathogenesis of schizophrenia in 22q11.2DS using cellular and mouse models indicates changes in expression of genes within the 22q11.2 deletion region and elsewhere in the genome, implicating molecular pathways involved in schizophrenia and associated neurocognitive deficits. Increased risks of obesity and of Parkinson's disease in 22q11.2DS warrant consideration in antipsychotic management. SUMMARY: Progress in characterizing and predicting psychotic illness in 22q11.2DS supports this identifiable subpopulation as a molecular model with important implications for understanding the pathogenesis of schizophrenia in the general population and for development of potential novel therapies.

Ectomycorrhizal Fungal Communities and Enzymatic Activities Vary across an Ecotone between a Forest and Field.

Extracellular enzymes degrade macromolecules into soluble substrates and are important for nutrient cycling in soils, where microorganisms, such as ectomycorrhizal (ECM) fungi, produce these enzymes to obtain nutrients. Ecotones between forests and fields represent intriguing arenas for examining the effect of the environment on ECM community structure and enzyme activity because tree maturity, ECM composition, and environmental variables may all be changing simultaneously. We studied the composition and enzymatic activity of ECM associated with loblolly pine (Pinus taeda) across an ecotone between a forest where P. taeda is established and an old field where P. taeda saplings had been growing for <5 years. ECM community and environmental characteristics influenced enzyme activity in the field, indicating that controls on enzyme activity may be intricately linked to the ECM community, but this was not true in the forest. Members of the Russulaceae were associated with increased phenol oxidase activity and decreased peroxidase activity in the field. Members of the Atheliaceae were particularly susceptible to changes in their abiotic environment, but this did not mediate differences in enzyme activity. These results emphasize the complex nature of factors that dictate the distribution of ECM and activity of their enzymes across a habitat boundary.