Anne Marie Higgins

Velo-cardio-facial syndrome

Purpose of review Velo-cardio-facial syndrome has emerged from obscurity to become one of the most researched disorders this past decade. It is one of the most common genetic syndromes in humans, the most common contiguous gene syndrome in humans, the most common syndrome of cleft palate, and the most common syndrome of conotruncal heart malformations. Velo-cardio-facial syndrome has an expansive phenotype, a factor reflected in the wide range of studies that cover both clinical features and molecular genetics. In this review, we cover multiple areas of research during the past year, including psychiatric disorders, neuroimaging, and the delineation of clinical features. Recent findings The identification of candidate genes for heart anomalies, mental illness, and other clinical phenotypes has been reported in the past year with a focus on TBX1 for cardiac and craniofacial phenotypes and COMT and PRODH for psychiatric disorders. The expansive phenotype of velo-cardio-facial syndrome continues to grow with new behavioral and structural anomalies reported. Treatment issues are beginning to draw attention, although most authors continue to focus on diagnostic issues. Summary Its high population prevalence, estimated to be as common as 1:2000 has sparked a large amount of research, as has the model the syndrome serves for identifying the causes of mental illness and learning disabilities, but it is obvious that more information is needed. Intensive scrutiny of velo-cardio-facial syndrome will undoubtedly continue for many years to come with the hope that researchers will turn more of their attention to treatment and treatment outcomes.

A gender-moderated effect of a functional COMT polymorphism on prefrontal brain morphology and function in velo-cardio-facial syndrome (22q11.2 deletion syndrome)

Caused by a microdeletion at the q11.2 locus of chromosome 22, velo‐cardio‐facial syndrome (also known as VCFS, 22q11 deletion syndrome, DiGeorge sequence, and conotruncal anomalies face syndrome) is associated with a distinctive physical, neurocognitive, and psychiatric phenotype. Increasing interest has centered on identifying the candidate genes within the deleted region that may contribute to this phenotype. One attractive candidate gene is catechol‐O‐methyltransferase (COMT) because it encodes for a protein that degrades dopamine. Variability in COMT activity is related to a Val158Met polymorphism that has been implicated in prefrontal lobe cognitive and neuropsychiatric function. We examined the effect of this polymorphism on prefrontal anatomy and frontally‐mediated neuropsychological function in 58 children with VCFS, 26 who were hemizygous for the Met allele and 32 for the Val allele. We found an allele by gender interaction effect on the volumes of the dorsal prefrontal and orbital prefrontal cortices. We did not find significant allele or gender by allele effects on neuropsychological tasks, although girls with the Met allele tended to perform better on the Wisconsin card sorting task. These data suggest that this functional COMT polymorphism may play a gender‐moderated role in determining the neuroanatomic phenotype of individuals with VCFS. Longitudinal evaluation of these children is essential in order to identify potential clinical implications of this allele by gender interaction.

Comparing phenotypes in patients with idiopathic autism to patients with velocardiofacial syndrome (22q11 DS) with and without autism

At least three research groups have reported that autism is diagnosed in up to 20% of children with velocardiofacial syndrome (VCFS). However the degree of phenotypic overlap between VCFS‐affected children with autism and those with idiopathic autism has not been established. The purpose of this study was to define and differentiate the behavioral phenotype of autism in samples of children with either (VCFS) or idiopathic autism. Five groups of children ages 5–15 were included in the between‐group design. Parent report of autism behaviors (based on the Autism Diagnostic Interview‐Revised, ADI‐R) were compared between children with VCFS, children with VCFS and autism (VCFS + autism), siblings of the children with VCFS, a community control group, and a group of children with idiopathic autism. Autism diagnoses were based according to the ADI‐R. Parental responses to the ADI‐R indicated that relative to children with VCFS‐only, children with idiopathic autism and children with VCFS + autism exhibited less make believe play and more rituals, motor stereotypies and repetitive use of objects. However several other core autism behaviors, including difficulties sharing attention, deficits in gestural communication and initiating conversation, and presence of circumscribed interests, appear to be phenotypic VCFS behaviors, characterizing children with VCFS regardless of an autism diagnosis. Accordingly, the autism phenotype in VCFS differs to some extent from that of idiopathic autism. Several features of idiopathic autism are spared in VCFS, and other features appear to be a function of the VCFS phenotype independent of autism. These findings carry implications for clinicians who diagnose and treat VCFS or autism, and for researchers who study genotype–phenotype associations in autism.

Neuroanatomic Predictors to Prodromal Psychosis in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome): A Longitudinal Study

BACKGROUND Up to 30% of young adults with velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) develop schizophrenia or psychosis. Identifying the neuroanatomic trajectories that increase risk for psychosis in youth with this genetic disorder is of great interest. METHODS We acquired high-resolution anatomic magnetic resonance images and measures of psychiatric function on 72 youth with VCFS, 26 unaffected siblings, and 24 age-matched community control subjects at two time points: between late childhood (mean age 11.9 years) and mid-adolescence (mean age 15.1 years). RESULTS With the exception of cranial gray matter and orbitofrontal prefrontal cortex, neuroanatomic trajectories in youth with VCFS were comparable to unaffected siblings and community control subjects during this developmental window. However, in youth with VCFS, longitudinal decreases in the volumes of cranial gray and white matter, prefrontal cortex, mesial temporal lobe, and cerebellum were associated with increased combined prodromal symptoms at Time 2. In contrast, only decreases in temporal lobe gray matter volumes (p < .002) and verbal IQ (p < .002) predicted specifically to positive prodromal symptoms of psychosis at Time 2. CONCLUSIONS These findings are in line with studies of non-VCFS individuals at risk for schizophrenia and suggest that early decrements in temporal lobe gray matter may be predictive of increased risk of prodromal psychotic symptoms in youth with VCFS.

Rhinovirus infection associated with serious illness among pediatric patients.

Rhinovirus is an important cause of respiratory infection among all age groups, but it is primarily thought of as being responsible for upper respiratory tract infection. Rhinovirus was isolated from the respiratory tract of 48 pediatric patients who were hospitalized (40) or seen in a pediatric emergency room (8) during the period of July, 1985, through December, 1988. Twenty-eight (58%) of the patients presented during the spring and early summer. Forty-one (86%) of the 48 patients were less than 12 months of age. All except four of the patients had viral cultures performed because of respiratory symptoms. Bronchiolitis was the single most frequent clinical diagnosis and was noted in equal proportion among children less than 3 months and 3 to 12 months of age. Nine patients were assigned a diagnosis of suspected sepsis. Rhinovirus infection was a complication of underlying illness for 17 (44%) of the 40 hospitalized patients, and those patients tended to be older than the otherwise healthy hospitalized infants with rhinovirus. Twenty-six patients (54%) were treated with antibacterial agents, although only one patient was documented to have a concomitant bacterial infection (Chlamydia trachomatis). Overall rhinovirus isolation during the study period represented 0.7% of all specimens submitted for viral isolation compared with 8.2% for respiratory syncytial virus. Rhinovirus infection leads to hospitalization less frequently than does respiratory syncytial virus infection, but the severity of illness and clinical presentation in young infants are similar.

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 22q11.2 could be responsible. To test this, a large sample size is needed. The TBX1 gene was sequenced in 360 consecutive 22q11DS patients. Rare and common variations were identified. We did not detect enrichment in rare SNP (single nucleotide polymorphism) number in those with or without a congenital heart defect. One exception was that there was increased number of very rare SNPs between those with normal heart anatomy compared to those with right‐sided aortic arch or persistent truncus arteriosus, suggesting potentially protective roles in the SNPs for these phenotype‐enrichment groups. Nine common SNPs (minor allele frequency, MAF > 0.05) were chosen and used to genotype the entire cohort of 1,022 22q11DS subjects. We did not find a correlation between common SNPs or haplotypes and cardiovascular phenotype. This work demonstrates that common DNA variations in TBX1 do not explain variable cardiovascular expression in 22q11DS patients, implicating existence of modifiers in other genes on 22q11.2 or elsewhere in the genome. Hum Mutat 32:1278–1289, 2011. ©2011 Wiley Periodicals, Inc.

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.

22q11.2DS deletion syndrome: developmental milestones in infants and toddlers.

Background: The majority of children with 22q11.2DS deletion syndrome (22q11.2DS) have learning disabilities, and a substantial number have mental retardation. Although cognitive data have been reported on several samples of children with 22q11.2DS, data on their early developmental milestones are limited. Methods: The present study used a retrospective design and asked parents to recall developmental milestones. The participants were 88 children with 22q11.2DS, 47 community controls, and 29 sibling controls. Results: Although very early gross motor and expressive language milestones did not differ significantly from comparison groups, subsequent gross motor and expressive language milestones did, suggesting that children with 22q11.2DS may begin to lag behind their peers sometime after the first year of life in these two domains. These patterns were also apparent when a subset of intellectually comparable children (22q11.2DS, n = 40 vs community controls, n = 24) was analyzed. We further found that receptive language and social adaptive milestones did not differ from comparison samples in either the early or later period. Receptive language delays were predictive of later Wechsler Intelligence Scale for Children-Third Edition Perceptual Organization Index scores, particularly in girls with 22q11.2DS. Conclusions: This suggests that although receptive language may be an area of relative strength in the developmental profile of young children with 22q11.2DS, even mild receptive delays should not be overlooked in early interventions with children with this disorder.

The Effects of Gender and Catechol O-Methyltransferase (COMT) Val108/158Met Polymorphism on Emotion Regulation in Velo-Cardio-Facial Syndrome (22q11.2 Deletion Syndrome): An fMRI Study

Velo-cardio-facial syndrome (VCFS) is caused by a micro-deletion of over 40 genes at the q11.2 locus of chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. COMT, one of the genes located in the deleted region, has been considered as a major candidate gene for genetic susceptibility in psychiatric diseases. Its functional polymorphism Val108/158Met has been shown to affect prefrontal function and working memory and has been associated with emotional dysregulation. We utilized a functional magnetic resonance imaging (fMRI) event-related paradigm to asses COMT genotype and gender-moderated effects on the neural activation that are elicited by viewing emotionally salient images charged with pleasant, unpleasant, and neutral content. Since estrogen down-regulates COMT activity resulting in lower COMT activity in women than men, we hypothesized an allele-by-gender interaction effect on neural activation. Participants included 43 VCFS individuals (Val/male=9, Val/female=17, Met/male=9, Met/female=8). We observed a gender effect on processing positive emotions, in that girls activated the cingulate gyrus more than boys did. We further observed a significant gender-by-allele interaction effect on neural function specific to the frontal lobe during the processing of pleasant stimuli, and specific to limbic regions during the processing of unpleasant stimuli. Our results suggest that in VCFS, the effect of the COMT Val108/158Met polymorphism is moderated by gender during the processing of emotional stimuli and could contribute to the understanding of the way in which this COMT polymorphism affects vulnerability to neuropsychiatric disorders.

Gender-moderated dorsolateral prefrontal reductions in 22q11.2 Deletion Syndrome: Implications for risk for schizophrenia

To investigate the impact of the microdeletion on morphology of the prefrontal cortex in 22q11.2 Deletion Syndrome (22q11.2 DS), high-resolution, anatomic magnetic resonance imaging was performed on 19 children and adolescents with 22q11.2 DS (11 females, 8 males) and 18 unaffected controls (10 females, 8 males). Tissue volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were measured. Tasks of executive function and working memory were administered to investigate the association between anatomy and function. Whole brain volume and frontal lobe tissue volume were preserved in girls but reduced in boys with 22q11.2 DS relative to age-matched controls. Dorsolateral prefrontal cortex (DLPFC) volumes were reduced in participants with 22q11.2 DS, although the gender-by-diagnosis effect found for frontal lobe was not as robust for DLPFC. DLPFC volumes were associated with performance on tasks of planning and emotional facial recognition. Longitudinal studies are needed to clarify whether gender differences in frontal lobe and DLPFC persist with development, and whether the volumes of the DLPFC are associated with eventual deterioration in adaptive/psychosocial function that may presage the onset of schizophrenia, for which individuals with 22q11.2 DS are at a disproportionately high risk.