Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era.

Schizophrenia is a complex neuropsychiatric disease with documented clinical and genetic heterogeneity, and evidence for neurodevelopmental origins. Driven by new genetic technologies and advances in molecular medicine, there has recently been concrete progress in understanding some of the specific genetic causes of this serious psychiatric illness. In particular, several large rare structural variants have been convincingly associated with schizophrenia, in targeted studies over two decades with respect to 22q11.

Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome.

Background: 22q11.2 deletion syndrome (22q11.2DS) is a common genetic subtype of intellectual disability (ID) remarkable for its constellation of congenital, developmental and later-onset features.

Evaluating genetic counseling for family members of individuals with schizophrenia in the molecular age.

Background: Myths and concerns about the extent and meaning of genetic risk in schizophrenia may contribute to significant stigma and burden for families. Genetic counseling has long been proposed to be a potentially informative and therapeutic intervention for schizophrenia. Surprisingly, however, available data are limited.

Overt cleft palate phenotype and TBX1 genotype correlations in velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients.

Velo-cardio-facial syndrome/DiGeorge syndrome, also known as 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome, with an estimated incidence of 1/2,000-1/4,000 live births. Approximately 9-11% of patients with this disorder have an overt cleft palate (CP), but the genetic factors responsible for CP in the 22q11DS subset are unknown.

1q21.1 Microduplication expression in adults.

Purpose: Rare, recurrent chromosome 1q21.1 duplications have been associated with developmental delay, congenital anomalies, and macrocephaly in children. Data on adult clinical expression would help to inform genetic counseling.

Rare copy number variations in adults with tetralogy of Fallot implicate novel risk gene pathways.

Structural genetic changes, especially copy number variants (CNVs), represent a major source of genetic variation contributing to human disease. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, but to date little is known about the role of CNVs in the etiology of TOF. Using high-resolution genome-wide microarrays and stringent calling methods, we investigated rare CNVs in a prospectively recruited cohort of 433 unrelated adults with TOF and/or pulmonary atresia at a single centre.

22q11.2 deletion syndrome: attitudes towards disclosing the risk of psychiatric illness.

22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with multisystem features.

Characterization of a multi-component anthrax vaccine designed to target the initial stages of infection as well as toxaemia.

Current vaccine approaches to combat anthrax are effective; however, they target only a single protein [the protective antigen (PA) toxin component] that is produced after spore germination. PA production is subsequently increased during later vegetative cell proliferation. Accordingly, several aspects of the vaccine strategy could be improved.

Functional outcomes of adults with 22q11.2 deletion syndrome.

Purpose: The 22q11.2 deletion syndrome is a common multisystem genomic disorder with congenital and later-onset manifestations, including congenital heart disease, intellectual disability, and psychiatric illness, that may affect long-term functioning. There are limited data on adult functioning in 22q11.

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43.

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males.

A Yersinia pestis YscN ATPase mutant functions as a live attenuated vaccine against bubonic plague in mice.

Yersinia pestis is the causative agent responsible for bubonic and pneumonic plague. The bacterium uses the pLcr plasmid-encoded type III secretion system to deliver virulence factors into host cells. Delivery requires ATP hydrolysis by the YscN ATPase encoded by the yscN gene also on pLcr.

Identification and properties of 1,119 candidate lincRNA loci in the Drosophila melanogaster genome.

The functional repertoire of long intergenic noncoding RNA (lincRNA) molecules has begun to be elucidated in mammals. Determining the biological relevance and potential gene regulatory mechanisms of these enigmatic molecules would be expedited in a more tractable model organism, such as Drosophila melanogaster. To this end, we defined a set of 1,119 putative lincRNA genes in D.

Early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition.

There are few studies of environmental factors in familial forms of schizophrenia. We investigated whether childhood adversity or environmental factors were associated with schizophrenia in a familial sample where schizophrenia is associated with the NOSA1P gene. We found that a cumulative adversity index including childhood illness, family instability and cannabis use was significantly associated with narrow schizophrenia, independent of NOSA1P risk genotype, previously measured childhood trauma, covariates and familial clustering (adjusted odds ratio (95% confidence interval)=1.

Extraordinary transgressive phenotypes of hybrid tomato are influenced by epigenetics and small silencing RNAs.

Hybrid organisms may fail to develop, be sterile or they may be more vigorous than either of the parents. Examples of hybrid vigour or hybrid necrosis in the F1 are often not inherited stably in subsequent generations if they are associated with overdominance. There can also be transgressive phenotypes that are inherited stably in these later generations, but the underlying mechanisms are not well understood.

Caregiver and adult patient perspectives on the importance of a diagnosis of 22q11.2 deletion syndrome.

Background: Recent advances in genetics are particularly relevant in the field of intellectual disability (ID), where sub-microscopic deletions or duplications of genetic material are increasingly implicated as known or suspected causal factors. Data-driven reports on the impact of providing an aetiological explanation in ID are needed to help justify widespread use of new and expensive genetic technologies.

Methods: We conducted a survey of caregivers on the value of a genetic/aetiologic diagnosis of 22q11.

Sex differences in reproductive fitness contribute to preferential maternal transmission of 22q11.2 deletions.

Background: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans.

Mobile 24 nt small RNAs direct transcriptional gene silencing in the root meristems of Arabidopsis thaliana.

RNA silencing in flowering plants generates a signal that moves between cells and through the phloem [1, 2]. Nucleotide sequence specificity of the signal is conferred by 21, 22, and 24 nucleotide (nt) sRNAs that are generated by Dicer-like (DCL) proteins [3]. In the recipient cells these sRNAs bind to Argonaute (AGO) effectors of silencing and the 21 nt sRNAs mediate posttranscriptional regulation (PTGS) via mRNA cleavage [4] whereas the 24 nt sRNAs are associated with RNA-dependent DNA methylation (RdDM) [5] that may underlie transcriptional gene silencing (TGS).

Genotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients.

Haploinsufficiency of TBX1, encoding a T-box transcription factor, is largely responsible for the physical malformations in velo-cardio-facial /DiGeorge/22q11.2 deletion syndrome (22q11DS) patients. Cardiovascular malformations in these patients are highly variable, raising the question as to whether DNA variations in the TBX1 locus on the remaining allele of 22q11.

Cognitive, behavioural and psychiatric phenotype in 22q11.2 deletion syndrome.

22q11.2 Deletion syndrome has become an important model for understanding the pathophysiology of neurodevelopmental conditions, particularly schizophrenia which develops in about 20-25% of individuals with a chromosome 22q11.2 microdeletion.

Association of schizophrenia in 22q11.2 deletion syndrome and gray matter volumetric deficits in the superior temporal gyrus.

Objective: Individuals with 22q11.2 deletion syndrome are known to be at high risk of developing schizophrenia. Previous imaging studies have provided limited data on the relation of schizophrenia expression in 22q11.