Aortopathy in the 7q11.23 microduplication syndrome

The 7q11.23 microduplication syndrome, caused by the reciprocal duplication of the Williams-Beuren syndrome deletion region, is a genomic disorder with an emerging clinical phenotype. Dysmorphic features, congenital anomalies, hypotonia, developmental delay highlighted by variable speech delay, and autistic features are characteristic findings. Congenital heart defects, most commonly patent ductus arteriosus, have been reported in a minority of cases. Included in the duplicated region is elastin (), implicated as the cause of supravalvar aortic stenosis in patients with Williams–Beuren syndrome. Here we present a series of eight pediatric patients and one adult with 7q11.23 microduplication syndrome, all of whom had aortic dilation, the opposite vascular phenotype of the typical supravalvar aortic stenosis found in Williams–Beuren syndrome. The ascending aorta was most commonly involved, while dilation was less frequently identified at the aortic root and sinotubular junction. The findings in these patients support a recommendation for cardiovascular surveillance in patients with 7q11.23 microduplication syndrome. © 2014 Wiley Periodicals, Inc

Survival of children with trisomy 13 and trisomy 18: A multi-state population-based study

Trisomy 13 (T13) and trisomy 18 (T18) are among the most prevalent autosomal trisomies. Both are associated with a very high risk of mortality. Numerous instances, however, of long-term survival of children with T13 or T18 have prompted some clinicians to pursue aggressive treatment instead of the traditional approach of palliative care. The purpose of this study is to assess current mortality data for these conditions. This multi-state, population-based study examined data obtained from birth defect surveillance programs in nine states on live-born infants delivered during 1999–2007 with T13 or T18. Information on children’s vital status and selected maternal and infant risk factors were obtained using matched birth and death certificates and other data sources. The Kaplan–Meier method and Cox proportional hazards models were used to estimate age-specific survival probabilities and predictors of survival up to age five. There were 693 children with T13 and 1,113 children with T18 identified from the participating states. Among children with T13, 5-year survival was 9.7%; among children with T18, it was 12.3%. For both trisomies, gestational age was the strongest predictor of mortality. Females and children of non-Hispanic black mothers had the lowest mortality. Omphalocele and congenital heart defects were associated with an increased risk of death for children with T18 but not T13. This study found survival among children with T13 and T18 to be somewhat higher than those previously reported in the literature, consistent with recent studies reporting improved survival following more aggressive medical intervention for these children

Maternal Exposure to Nitrogen Dioxide, Intake of Methyl Nutrients, and Congenital Heart Defects in Offspring

Nutrients that regulate methylation processes may modify susceptibility to the effects of air pollutants. Data from the National Birth Defects Prevention Study (United States, 1997-2006) were used to estimate associations between maternal exposure to nitrogen dioxide (NO2), dietary intake of methyl nutrients, and the odds of congenital heart defects in offspring. NO2 concentrations, a marker of traffic-related air pollution, averaged across postconception weeks 2-8, were assigned to 6,160 nondiabetic mothers of cases and controls using inverse distance-squared weighting of air monitors within 50 km of maternal residences. Intakes of choline, folate, methionine, and vitamins B6 and B12 were assessed using a food frequency questionnaire. Hierarchical regression models, which accounted for similarities across defects, were constructed, and relative excess risks due to interaction were calculated. Relative to women with the lowest NO2 exposure and high methionine intake, women with the highest NO2 exposure and lowest methionine intake had the greatest odds of offspring with a perimembranous ventricular septal defect (odds ratio = 3.23, 95% confidence interval: 1.74, 6.01; relative excess risk due to interaction = 2.15, 95% confidence interval: 0.39, 3.92). Considerable departure from additivity was not observed for other defects. These results provide modest evidence of interaction between nutrition and NO2 exposure during pregnancy

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures

Maternal Exposure to Criteria Air Pollutants and Congenital Heart Defects in Offspring: Results from the National Birth Defects Prevention Study

Background: Epidemiologic literature suggests that exposure to air pollutants is associated with fetal development

Small Deletions of SATB2 Cause Some of the Clinical Features of the 2q33.1 Microdeletion Syndrome

Recurrent deletions of 2q32q33 have recently been reported as a new microdeletion syndrome. Clinical features of this syndrome include severe mental retardation, growth retardation, dysmorphic features, thin and sparse hair, feeding difficulties and cleft or high palate. The commonly deleted region contains at least seven genes. Haploinsufficiency of one of these genes, SATB2, a DNA-binding protein that regulates gene expression, has been implicated as causative in the cleft or high palate of individuals with 2q32q33 microdeletion syndrome. In this study we describe three individuals with smaller microdeletions of this region, within 2q33.1. The deletions ranged in size from 173.1 kb to 185.2 kb and spanned part of SATB2. Review of clinical records showed similar clinical features among these individuals, including severe developmental delay and tooth abnormalities. Two of the individuals had behavioral problems. Only one of the subjects presented here had a cleft palate, suggesting reduced penetrance for this feature. Our results suggest that deletion of SATB2 is responsible for several of the clinical features associated with 2q32q33 microdeletion syndrome

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

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High Density SNP Screen in A Large Multiplex Neural Tube Defect Family Refines Linkage to Loci at 7p21-Pter And 2q33.1-35

Neural tube defects (NTDs) are considered complex with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs (Rampersaud et al. 2005) demonstrated evidence of linkage to chromosomes 7 and 10. This screen included forty-four multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7

The Study to Explore Early Development (SEED): A Multisite Epidemiologic Study of Autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network

The Study to Explore Early Development (SEED), a multisite investigation addressing knowledge gaps in autism phenotype and etiology, aims to: (1) characterize the autism behavioral phenotype and associated developmental, medical, and behavioral conditions and (2) investigate genetic and environmental risks with emphasis on immunologic, hormonal, gastrointestinal, and sociodemographic characteristics. SEED uses a case–control design with population-based ascertainment of children aged 2–5 years with an autism spectrum disorder (ASD) and children in two control groups—one from the general population and one with non-ASD developmental problems. Data from parent-completed questionnaires, interviews, clinical evaluations, biospecimen sampling, and medical record abstraction focus on the prenatal and early postnatal periods. SEED is a valuable resource for testing hypotheses regarding ASD characteristics and causes

Molecular and Clinical Analyses of Greig Cephalopolysyndactyly and Pallister-Hall Syndromes: Robust Phenotype Prediction from the Type and Position of GLI3 Mutations

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1–1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998–3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3′ third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis