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1.  Atypical Presentation of Moyamoya Disease in an Infant with a de novo RNF213 Variant 
Variants in RNF213 lead to susceptibility to moyamoya disease, a rare cerebral angiopathy characterized by bilateral stenosis of the internal carotid arteries and development of a compensatory collateral network. We describe a 3-month-old female with seizures, arterial narrowing involving the internal carotid and intracranial arteries and inferior abdominal aorta, and persistently elevated transaminases. Whole exome sequencing demonstrated a novel de novo variant in RNF213, securing a molecular diagnosis and directing appropriate intervention. This report underscores the role of whole exome sequencing in cases for which a complex and atypical presentation may mask diagnosis. Furthermore, the early and severe presentation in our patient, in conjunction with a novel de novo RNF213 variant, suggests that specific variants in RNF213 may lead to a Mendelian form of disease rather than simply conferring susceptibility to multifactorial disease.
PMCID: PMC4639746  PMID: 26198278
Moyamoya disease; RNF213; whole exome sequencing
2.  Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene 
Previously rare A2ML1 variants were identified to confer otitis media susceptibility in an indigenous Filipino community and in otitis-prone US children. The goal of this study is to describe differences in the middle ear microbiome between carriers and non-carriers of an A2ML1 duplication variant that increases risk for chronic otitis media among indigenous Filipinos with poor health care access.
Ear swabs were obtained from 16 indigenous Filipino individuals with chronic otitis media, of whom 11 carry the A2ML1 duplication variant. Ear swabs were submitted for 16S rRNA gene sequencing.
Genotype-based differences in microbial richness, structure, and composition were identified, but were not statistically significant. Taxonomic analysis revealed that the relative abundance of the phyla Fusobacteria and Bacteroidetes, and genus Fusobacterium were nominally increased in carriers compared to non-carriers, but were non-significant after correction for multiple testing. We also detected rare bacteria including Oligella that was reported only once in the middle ear.
These findings suggest that A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome. Knowledge of middle ear microbial profiles according to genetic background can be potentially useful for therapeutic and prophylactic interventions for otitis media and can guide public health interventions towards decreasing otitis media prevalence within the indigenous Filipino community.
Electronic supplementary material
The online version of this article (doi:10.1186/s40249-016-0189-7) contains supplementary material, which is available to authorized users.
PMCID: PMC5088646  PMID: 27799062
A2ML1; Indigenous population; Microbiome; Middle ear; Oligella; Otitis media; Philippines
5.  Toward clinical genomics in everyday medicine: perspectives and recommendations 
Precision or personalized medicine through clinical genome and exome sequencing has been described by some as a revolution that could transform healthcare delivery, yet it is currently used in only a small fraction of patients, principally for the diagnosis of suspected Mendelian conditions and for targeting cancer treatments. Given the burden of illness in our society, it is of interest to ask how clinical genome and exome sequencing can be constructively integrated more broadly into the routine practice of medicine for the betterment of public health. In November 2014, 46 experts from academia, industry, policy and patient advocacy gathered in a conference sponsored by Illumina, Inc. to discuss this question, share viewpoints and propose recommendations. This perspective summarizes that work and identifies some of the obstacles and opportunities that must be considered in translating advances in genomics more widely into the practice of medicine.
PMCID: PMC4841021  PMID: 26810587
Personalized medicine; precision medicine; clinical genomics; practice standards; genomic data; exome; genome; sequencing; genetic testing
6.  Nutritional and Metabolic Biomarkers in Autism Spectrum Disorders: An Exploratory Study 
Autism spectrum disorder (ASD) is currently on the rise, now affecting approximately 1 in 68 children in the United States according to a 2010 surveillance summary from the Centers for Disease Control and Prevention (CDC). This figure is an estimated increase of 78% from the figure in 2002. The CDC suggests that more investigation is needed to understand this astounding increase in autism in such a short period.
The aim of this pilot study was to determine whether a group of children with ASD exhibited similar variations in a broad array of potential correlates, including medical histories, symptoms, genetics, and multiple nutritional and metabolic biomarkers.
This study was a retrospective, descriptive chart review.
The study took place at the University of Kansas Medical Center (KUMC).
Participants were 7 children with ASD who had sought treatment at the Integrative Medicine Clinic at the medical center.
A majority of the children exhibited an elevated copper:zinc ratio and abnormal vitamin D levels. Children also demonstrated abnormal levels of the essential fatty acids: (1) α-linolenic acid (ALA)— C13:3W3, and (2) linoleic acid (LA)—C18:2W6; high levels of docosahexaenoic acid (DHA); and an elevated ω-6:ω-3 ratio. Three of 7 children demonstrated abnormal manganese levels. Children did not demonstrate elevated urine pyruvate or lactate but did have abnormal detoxification markers. Three of 7 patients demonstrated abnormalities in citric acid metabolites, bacterial metabolism, and fatty acid oxidation markers. A majority demonstrated elevated serum immunoglobulin G (IgG) antibodies to casein, egg whites, egg yolks, and peanuts. A majority had absent glutathione S-transferase (GSTM) at the 1p13.3 location, and 3 of 7 children were heterozygous for the glutathione S-transferase I105V (GSTP1). A majority also exhibited genetic polymorphism of the mitochondrial gene superoxide dismutase A16V (SOD2).
The findings from this small group of children with ASD points to the existence of nutritional, metabolic, and genetic correlates of ASD. These factors appear to be important potential abnormalities that warrant a case control study to evaluate their reliability and validity as markers of ASD.
PMCID: PMC4566479  PMID: 26770138
7.  Genetic Basis of Congenital Cardiovascular Malformations 
Cardiovascular malformations are a singularly important class of birth defects and, due to dramatic improvements in medical and surgical care, there are now large numbers of adult survivors. The etiologies are complex, but there is strong evidence that genetic factors play a crucial role. Over the last 15 years there has been enormous progress in the discovery of causative genes for syndromic heart malformations and in rare families with Mendelian forms. The rapid characterization of genomic disorders as major contributors to congenital heart defects is also notable. The genes identified encode many transcription factors, chromatin regulators, growth factors and signal transduction pathways– all unified by their required roles in normal cardiac development. Genome-wide sequencing of the coding regions promises to elucidate genetic causation in several disorders affecting cardiac development. Such comprehensive studies evaluating both common and rare variants would be essential in characterizing gene-gene interactions, as well as in understanding the gene-environment interactions that increase the susceptibility to congenital heart defects.
PMCID: PMC4152939  PMID: 24793338
Congenital Heart Defect; Cardiac Development; Chromosomal and single gene disorders; Genomic Disorder
8.  Host Transcriptional Response to Influenza and Other Acute Respiratory Viral Infections – A Prospective Cohort Study 
PLoS Pathogens  2015;11(6):e1004869.
To better understand the systemic response to naturally acquired acute respiratory viral infections, we prospectively enrolled 1610 healthy adults in 2009 and 2010. Of these, 142 subjects were followed for detailed evaluation of acute viral respiratory illness. We examined peripheral blood gene expression at 7 timepoints: enrollment, 5 illness visits and the end of each year of the study. 133 completed all study visits and yielded technically adequate peripheral blood microarray gene expression data. Seventy-three (55%) had an influenza virus infection, 64 influenza A and 9 influenza B. The remaining subjects had a rhinovirus infection (N = 32), other viral infections (N = 4), or no viral agent identified (N = 24). The results, which were replicated between two seasons, showed a dramatic upregulation of interferon pathway and innate immunity genes. This persisted for 2-4 days. The data show a recovery phase at days 4 and 6 with differentially expressed transcripts implicated in cell proliferation and repair. By day 21 the gene expression pattern was indistinguishable from baseline (enrollment). Influenza virus infection induced a higher magnitude and longer duration of the shared expression signature of illness compared to the other viral infections. Using lineage and activation state-specific transcripts to produce cell composition scores, patterns of B and T lymphocyte depressions accompanied by a major activation of NK cells were detected in the acute phase of illness. The data also demonstrate multiple dynamic gene modules that are reorganized and strengthened following infection. Finally, we examined pre- and post-infection anti-influenza antibody titers defining novel gene expression correlates.
Author Summary
Gene expression profiling of human blood cells might uncover the complex dynamics of host response to ARIs such as pandemic H1N1. However, only limited data are available on the system level response to naturally acquired infections. To understand the molecular bases and network orchestration of host responses, we prospectively enrolled 1610 healthy adults in the fall of 2009 and 2010, followed the subjects with influenza-like illness (N = 133) for 3 weeks, and examined changes in their peripheral blood gene expression. We discovered distinct phases of the host response spanning 6 days after infection, and identified genes that differentiate influenza from non-influenza virus infection. We then moved the focus from gene expression patterns to gene co-expression patterns. We detected gene modules that are related to core features of regulatory networks and found a substantial increase in the connectivity of the influenza responsive genes. Finally, we identified a molecular signature that correlated significantly with antibody response to pH1N1 virus. Taken together, our findings offer insights into the molecular mechanisms underlying host response to influenza virus infection, and provide a valuable foundation for investigation of the global coordinated responses to ARIs. Molecular correlates of the immune response suggest targets for intervention and improved vaccines.
PMCID: PMC4466531  PMID: 26070066
9.  Laterality Defects in the National Birth Defects Prevention Study (1998–2007): Birth Prevalence and Descriptive Epidemiology 
Little is known epidemiologically about laterality defects. Using data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, we analyzed prevalence and selected characteristics in children born with laterality defects born from 1998 to 2007. We identified 517 nonsyndromic cases (378 heterotaxy, 73.1%; 139 situs inversus totalis [SIT], 26.9%) resulting in an estimated birth prevalence of 1.1 per 10,000 live births (95% confidence interval 1.0–1.2). Prevalence did not differ significantly across sites, over time, or by inclusion of pregnancy termination. Laterality defects were more common among preterm cases compared to term cases, and in children born to mothers who were non-white or younger than 20 years compared to white mothers or those age 25–29 years. The distribution of associated cardiac and extracardiac defects, excluding the expected heterotaxy anomalies, varied by type of laterality defect. Cases with heterotaxy were significantly more likely than those with SIT to have double outlet right ventricle, atrioventricular canal defects, pulmonary stenosis, non-tetralogy of Fallot pulmonary atresia with ventricular septal defect, totally and partially anomalous pulmonary venous return; also more likely to have orofacial clefts, esophageal atresia, bowel atresias, and omphalocele, though not reaching statistical significance. Relatively more common among cases with SIT were Dandy-Walker malformation, anotia/microtia, and limb deficiency. The similarity in the demographic characteristics of heterotaxy and SIT supports the hypothesis that they are part of a continuum of abnormal left-right axis patterning. These findings on laterality defects may help guide clinical care, future research, and prevention strategies.
PMCID: PMC4462240  PMID: 25099286
asplenia; cardiovascular malformations; congenital heart defects; dextrocardia; heterotaxy; isomerism; laterality defects; malposition; prevalence; race/ethnic disparities; situs ambiguous; situs inversus
10.  A Genome-Wide Screen for Large-Effect Alloimmunization Susceptibility Loci among Red Blood Cell Transfusion Recipients with Sickle Cell Disease 
A selective susceptibility of certain individuals to form multiple alloantibodies in response to red cell transfusion is well-recognized in clinical practice, and is a particular problem in persons with sickle cell disease (SCD). The reason for this differential susceptibility is unclear, but inter-individual genetic differences are likely to contribute.
We conducted a pilot case-control genome-wide association study using 1,000,000 SNPs in 94 alloimmune responders (cases) and non-responders (controls) with SCD in order to identify loci of large effect size associated with alloimmunization.
No loci showed evidence of association at a genome-wide significance cut-off (p < 0.5 × 10–8). SNPs in the ARAP1/STARD10 region showed suggestive association (p < 1 × 10–6), but no association was observed at previously implicated loci TRIM21 or HLA. In analyses of the number of accumulated antibodies, a modest association was found with SNPs in the Toll-like receptor gene TLR10 (p < 1 × 10–4).
Alloimmunization in persons with SCD is unlikely to be mediated by loci of very large effect size; however, larger and more comprehensive studies are required to fully evaluate loci with more moderate effects. This study provides a working approach to such future studies in SCD.
PMCID: PMC4280456  PMID: 25670933
Genome-wide association studies; GWAS; African American; Responders; Genomics
11.  MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development 
Human Molecular Genetics  2013;22(21):4339-4348.
Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene, MCTP2 (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a de novo 41 kb intragenic duplication within MCTP2, predicted to result in premature truncation, p.F697X. Alteration of Mctp2 gene expression in Xenopus laevis embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify MCTP2 as a novel genetic cause of CoA and related cardiac malformations.
PMCID: PMC3792692  PMID: 23773997
12.  Replicative mechanisms for CNV formation are error prone 
Nature genetics  2013;45(11):1319-1326.
We investigated 67 breakpoint junctions of gene copy number gains (CNVs) in 31 unrelated subjects. We observed a strikingly high frequency of small deletions and insertions (29%) apparently originating from polymerase-slippage events, in addition to frameshifts and point mutations in homonucleotide runs (13%), at or flanking the breakpoint junctions of complex CNVs. These simple nucleotide variants (SNV) were generated concomitantly with the de novo complex genomic rearrangement (CGR) event. Our findings implicate a low fidelity error-prone DNA polymerase in synthesis associated with DNA repair mechanisms that leads to a local increase in point mutation burden associated with human CGR.
PMCID: PMC3821386  PMID: 24056715
MMBIR; FoSTeS; MECP2; duplication; complex rearrangements; triplication; CNVs
13.  Comparative Analyses of Lung Transcriptomes in Patients with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins and in Foxf1 Heterozygous Knockout Mice 
PLoS ONE  2014;9(4):e94390.
Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a developmental disorder of the lungs, primarily affecting their vasculature. FOXF1 haploinsufficiency due to heterozygous genomic deletions and point mutations have been reported in most patients with ACDMPV. The majority of mice with heterozygous loss-of-function of Foxf1 exhibit neonatal lethality with evidence of pulmonary hemorrhage in some of them. By comparing transcriptomes of human ACDMPV lungs with control lungs using expression arrays, we found that several genes and pathways involved in lung development, angiogenesis, and in pulmonary hypertension development, were deregulated. Similar transcriptional changes were found in lungs of the postnatal day 0.5 Foxf1+/− mice when compared to their wildtype littermate controls; 14 genes, COL15A1, COL18A1, COL6A2, ESM1, FSCN1, GRINA, IGFBP3, IL1B, MALL, NOS3, RASL11B, MATN2, PRKCDBP, and SIRPA, were found common to both ACDMPV and Foxf1 heterozygous lungs. Our results advance knowledge toward understanding of the molecular mechanism of ACDMPV, lung development, and its vasculature pathology. These data may also be useful for understanding etiologies of other lung disorders, e.g. pulmonary hypertension, bronchopulmonary dysplasia, or cancer.
PMCID: PMC3983164  PMID: 24722050
14.  A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human 
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare developmental lung disorder that is uniformly lethal. Affected infants die within the first few weeks of their life despite aggressive treatment, although a few cases of late manifestation and longer survival have been reported. We have shown previously that mutations and deletions in FOXF1 are a cause of this disorder. Although most of the cases of ACD/MPV are sporadic, there have been infrequent reports of familial cases. We present a family with five out of six children affected with ACD/MPV. DNA analysis identified a missense mutation (c.416G>T; p.Arg139Leu) in the FOXF1 gene that segregated in the three affected siblings tested. The same variant is also present as a de novo mutation in the mother and arose on her paternally derived chromosome 16. The two tested affected siblings share the same chromosome 16 haplotype inherited from their maternal grandfather. Their single healthy sibling has a different chromosome 16 haplotype inherited from the maternal grandmother. The results are consistent with paternal imprinting of FOXF1 in human.
PMCID: PMC3598325  PMID: 22990143
ACD/MPV; FOXF1; imprinting; angiogenesis; lung development
15.  Antibody Correlates and Predictors of Immunity to Naturally Occurring Influenza in Humans and the Importance of Antibody to the Neuraminidase 
The Journal of Infectious Diseases  2013;207(6):974-981.
Background. Serum antibody to the hemagglutinin (HA) of influenza viruses is a correlate and predictor of immunity to influenza in humans; the relative values of other correlates are uncertain.
Methods. Serum and nasal secretions (NS) were collected in fall and spring of 2009–2011 from healthy adults who were monitored for acute respiratory illness (ARI). Serum samples were tested for hemagglutination-inhibition (HAI) antibody increase and secretions for virus if ill; enrollment sera were also tested for neuraminidase-inhibiting (NI) antibody and NS for neutralizing (neut), NI, immunoglobulin A (IgA), and immunoglobulin G (IgG) anti-HA antibody.
Results. Serum anti-HA and anti-neuraminidase (NA) antibody titers to 2009(H1N1) pandemic influenza virus (pH1N1) correlated with titers in NS (including IgA and IgG antibody). Increasing anti-HA and anti-NA titers in serum and NS tests all correlated with reducing infection and infection-associated illness. Multivariate analyses indicated serum HAI and NI each independently predicted immunity to infection and infection-associated illness. Only serum NI independently predicted reduced illness among infected subjects.
Conclusions. Increasing anti-HA and NA antibody in serum and secretions correlated with reducing pH1N1 influenza virus infection and illness in healthy young adults. Both anti-HA and anti-NA antibody are independent predictors of immunity to influenza; ensuring induction of both by vaccination is desirable.
PMCID: PMC3633450  PMID: 23307936
influenza; hemagglutinin; neuraminidase; antibody; immunity
16.  Zic3 is required in the extra-cardiac perinodal region of the lateral plate mesoderm for left–right patterning and heart development 
Human Molecular Genetics  2012;22(5):879-889.
Mutations in ZIC3 cause human X-linked heterotaxy and isolated cardiovascular malformations. A mouse model with targeted deletion of Zic3 demonstrates an early role for Zic3 in gastrulation, CNS, cardiac and left–right axial development. The observation of multiple malformations in Zic3null mice and the relatively broad expression pattern of Zic3 suggest its important roles in multiple developmental processes. Here, we report that Zic3 is primarily required in epiblast derivatives to affect left–right patterning and its expression in epiblast is necessary for proper transcriptional control of embryonic cardiac development. However, cardiac malformations in Zic3 deficiency occur not because Zic3 is intrinsically required in the heart but rather because it functions early in the establishment of left–right body axis. In addition, we provide evidence supporting a role for Zic3 specifically in the perinodal region of the posterior lateral plate mesoderm for the establishment of laterality. These data delineate the spatial requirement of Zic3 during left–right patterning in the mammalian embryo, and provide basis for further understanding the molecular mechanisms underlying the complex interaction of Zic3 with signaling pathways involved in the early establishment of laterality.
PMCID: PMC3606008  PMID: 23184148
17.  NPHP4 Variants are Associated with Pleiotropic Heart Malformations 
Circulation research  2012;110(12):1564-1574.
Congenital heart malformations are a major cause of morbidity and mortality especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs.
To identify genetic mutations causing cardiac laterality defects.
Methods and Results
We performed a genome-wide linkage analysis in patients with cardiac laterality defects from a consanguineous family. The patients had combinations of defects that included dextrocardia, transposition of great arteries, double outlet right ventricle, atrio-ventricular septal defects and caval vein abnormalities. Sequencing of positional candidate genes identified mutations in NPHP4. We performed mutation analysis of NPHP4 in 146 unrelated patients with similar cardiac laterality defects. Forty-one percent of these patients also had laterality defects of the abdominal organs. We identified eight additional missense variants that were absent or very rare in controls. To study the role of nphp4 in establishing L-R asymmetry, we used antisense morpholinos to knockdown nphp4 expression in zebrafish. Depletion of nphp4 disrupted L-R patterning as well as cardiac and gut laterality. Cardiac laterality defects were partially rescued by human NPHP4 mRNA, whereas mutant NPHP4 containing genetic variants found in patients failed to rescue. We show that nphp4 is involved in the formation of motile cilia in Kupffer’s vesicle (KV), which generate asymmetric fluid flow necessary for normal L-R asymmetry.
NPHP4 mutations are associated with cardiac laterality defects and heterotaxy. In zebrafish, nphp4 is essential for the development and function of KV cilia and is required for global L-R patterning.
PMCID: PMC3916111  PMID: 22550138
Congenital heart malfortmations; heterotaxy; nphp4; cilia; zebrafish
18.  Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities 
Clinically significant cardiovascular malformations (CVMs) occur in 5–8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs). Through a genome-wide survey of 203 subjects with CVMs and ECAs, we identified 55 CNVs >50 kb in length that were not present in children without known cardiovascular defects (n=872). Sixteen unique CNVs overlapping these variants were found in an independent CVM plus ECA cohort (n=511), which were not observed in 2011 controls. The study identified 12/16 (75%) novel loci including non-recurrent de novo 16q24.3 loss (4/714) and de novo 2q31.3q32.1 loss encompassing PPP1R1C and PDE1A (2/714). The study also narrowed critical intervals in three well-recognized genomic disorders of CVM, such as the cat-eye syndrome region on 22q11.1, 8p23.1 loss encompassing GATA4 and SOX7 and 17p13.3-p13.2 loss. An analysis of protein-interaction databases shows that the rare inherited and de novo CNVs detected in the combined cohort are enriched for genes encoding proteins that are direct or indirect partners of proteins known to be required for normal cardiac development. Our findings implicate rare variants such as 16q24.3 loss and 2q31.3-q32.1 loss, and delineate regions within previously reported structural variants known to cause CVMs.
PMCID: PMC3548268  PMID: 22929023
rare copy number variations; extracardiac anomalies (ECAs); cardiovascular malformations (CVMs); 16q24.3 microdeletion; protein-interaction network
19.  Headstrong intervention for pediatric migraine headache: a randomized clinical trial 
The purpose of this study was to evaluate the efficacy of a self-guided CD-ROM program (“Headstrong”) containing cognitive-behavioral self-management strategies versus an educational CD-ROM program for treating headaches, headache-related disability, and quality of life.
Participants were 35 children ages 7–12 years with migraine recruited from one university medical center and two children’s hospital headache clinics. Participants were randomly assigned to complete the Headstrong or educational control CD-ROM program over a 4-week period. Data on headache frequency, duration, and severity, migraine-related disability, and quality of life (QOL) were obtained at baseline, post-intervention, and 3-months post-intervention.
At post-intervention, Headstrong resulted in lower severity (on a 10-point scale) than the control group by child report (5.06 ± 1.50 SD vs. 6.25 ± 1.92 SD, p = 0.03, ES = 0.7). At 3-months post-intervention, parents reported less migraine-related disability (on the PedMIDAS) in the Headstrong group compared to the control group (1.36 ± 2.06 SD vs. 5.18 ± 6.40 SD; p = 0.04, ES = 0.8). There were no other group differences at post treatment or at 3-months post-intervention.
When compared to an educational control, Headstrong resulted in lower pain severity at post-treatment and less migraine-related disability at 3-months post-intervention, by child and parent report respectively. Headache frequency and quality of life did not change more for Headstrong versus control. Additional research is needed on the Headstrong Program to increase its efficacy and to test it with a larger sample recruited from multiple centers simultaneously.
PMCID: PMC3996073  PMID: 24580721
Headache; Children; Migraine; Behavioral treatments; E-health; CD-ROM; Child; Migraine headaches; Cognitive-behavioral treatment
20.  Assessment of Bone Mineral Status in Children with Marfan syndrome 
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with skeletal involvement. It is caused by mutations in fibrillin1 (FBN1) gene resulting in activation of TGF-β, which developmentally regulates bone mass and matrix properties. There is no consensus regarding bone mineralization in children with MFS. Using dual-energy X-ray absorptiometry (DXA) we evaluated bone mineralization in 20 children with MFS unselected for bone problems. Z-scores were calculated based on age, gender, height, and ethnicity matched controls. Mean whole body bone mineral content (BMC) z-score was 0.26 ± 1.42 (p=0.41). Mean bone mineral density (BMD) z-score for whole body was −0.34 ± 1.4 (p=0.29) and lumbar spine was reduced at −0.55 ± 1.34 (p=0.017). On further adjusting for stature, which is usually higher in MFS, mean BMC z-score was reduced at −0.677 ± 1.37 (p=0.04), mean BMD z-score for whole body was −0.82 ± 1.55 (p=0.002) and for lumbar spine was −0.83 ± 1.32 (p=0.001). An increased risk of osteoporosis in MFS is controversial. DXA has limitations in large skeletons because it tends to overestimate BMD and BMC. By adjusting results for height, age, gender, and ethnicity, we found that MFS patients have significantly lower BMC and BMD in whole body and lumbar spine. Evaluation of diet, exercise, vitamin D status, and bone turnover markers will help gain insight into pathogenesis of the reduced bone mass. Further, larger longitudinal studies are required to evaluate the natural history, incidence of fractures and effects of pharmacological therapy.
PMCID: PMC3429634  PMID: 22887731
Marfan syndrome; Bone mineral density; TGF-β
21.  Impact of restricted marital practices on genetic variation in an endogamous Gujarati group 
Recent studies have examined the influence on patterns of human genetic variation of a variety of cultural practices. In India, centuries-old marriage customs have introduced extensive social structuring into the contemporary population, potentially with significant consequences for genetic variation. Social stratification in India is evident as social classes that are defined by endogamous groups known as castes. Within a caste, there exist endogamous groups known as gols (marriage circles), each of which comprises a small number of exogamous gotra (lineages). Thus, while consanguinity is strictly avoided and some randomness in mate selection occurs within the gol, gene flow is limited with populations outside the gol. Gujarati Patels practice this form of “exogamic endogamy.” We have analyzed genetic variation in one such group of Gujarati Patels, the Chha Gaam Patels (CGP), who comprise individuals from six villages. Population structure analysis of 1,200 autosomal loci offers support for the existence of distinctive multilocus genotypes in the CGP with respect to both non-Gujaratis and other Gujaratis, and indicates that CGP individuals are genetically very similar. Analysis of Y-chromosomal and mitochondrial haplotypes provides support for both patrilocal and patrilineal practices within the gol, and a low-level of female gene flow into the gol. Our study illustrates how the practice of gol endogamy has introduced fine-scale genetic structure into the population of India, and contributes more generally to an understanding of the way in which marriage practices affect patterns of genetic variation.
PMCID: PMC3436606  PMID: 22729696
Endogamy; Gene Flow; HVS1; India; Y-chromosomal
22.  Association of Common Variants in ERBB4 with Congenital Left Ventricular Outflow Tract Obstruction Defects 
The left ventricular outflow tract (LVOT) defects aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS) represent an embryologically related group of congenital cardiovascular malformations. They are common and cause substantial morbidity and mortality. Prior evidence suggests a strong genetic component in their causation.
We selected NRG1, ERBB3, and ERBB4 of the epidermal growth factor receptor (EGFR) signaling pathway as candidate genes for investigation of association with LVOT defects based on the importance of this pathway in cardiac development and the phenotypes in knockout mouse models. Single nucleotide polymorphism (SNP) genotyping was performed on 343 affected case-parent trios of European ancestry.
We identified a specific haplotype in intron 3 of ERBB4 that was positively associated with the combined LVOT defects phenotype (p = 0.0005) and in each anatomic defect AVS, COA, and HLHS separately. Mutation screening of individuals with an LVOT defect failed to identify a coding sequence or splice site change in ERBB4. RT-PCR on lymphoblastoid cells from LVOT subjects did not show altered splice variant ratios among those homozygous for the associated haplotype.
These results suggest ERBB4 is associated with LVOT defects. Further replication will be required in separate cohorts to confirm the consistency of the observed association.
PMCID: PMC3736588  PMID: 21290564
genetics of cardiovascular disease; heart defects; congenital; congenital abnormalities; cardiovascular abnormalities; analysis; genetic association
23.  Small rare recurrent deletions and reciprocal duplications in 2q21.1, including brain-specific ARHGEF4 and GPR148 
Human Molecular Genetics  2012;21(15):3345-3355.
We have identified a rare small (∼450 kb unique sequence) recurrent deletion in a previously linked attention-deficit hyperactivity disorder (ADHD) locus at 2q21.1 in five unrelated families with developmental delay (DD)/intellectual disability (ID), ADHD, epilepsy and other neurobehavioral abnormalities from 17 035 samples referred for clinical chromosomal microarray analysis. Additionally, a DECIPHER ( patient 2311 was found to have the same deletion and presented with aggressive behavior. The deletion was not found in either six control groups consisting of 13 999 healthy individuals or in the DGV database. We have also identified reciprocal duplications in five unrelated families with autism, developmental delay (DD), seizures and ADHD. This genomic region is flanked by large, complex low-copy repeats (LCRs) with directly oriented subunits of ∼109 kb in size that have 97.7% DNA sequence identity. We sequenced the deletion breakpoints within the directly oriented paralogous subunits of the flanking LCR clusters, demonstrating non-allelic homologous recombination as a mechanism of formation. The rearranged segment harbors five genes: GPR148, FAM123C, ARHGEF4, FAM168B and PLEKHB2. Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function. GPR148 encodes a G-protein-coupled receptor protein expressed in the brain and testes. We suggest that small rare recurrent deletion of 2q21.1 is pathogenic for DD/ID, ADHD, epilepsy and other neurobehavioral abnormalities and, because of its small size, low frequency and more severe phenotype might have been missed in other previous genome-wide screening studies using single-nucleotide polymorphism analyses.
PMCID: PMC3392111  PMID: 22543972
24.  Specific Association of Missense Mutations in CRELD1 with Cardiac Atrioventricular Septal Defects in Heterotaxy Syndrome 
PMCID: PMC3402694  PMID: 22740159
congenital heart defects; atrioventricular septal defect; genetic etiology; heterotaxy syndrome; complex genetic disease; laterality defects
25.  Integrative genomic analysis of the human immune response to influenza vaccination 
eLife  null;2:e00299.
Identification of the host genetic factors that contribute to variation in vaccine responsiveness may uncover important mechanisms affecting vaccine efficacy. We carried out an integrative, longitudinal study combining genetic, transcriptional, and immunologic data in humans given seasonal influenza vaccine. We identified 20 genes exhibiting a transcriptional response to vaccination, significant genotype effects on gene expression, and correlation between the transcriptional and antibody responses. The results show that variation at the level of genes involved in membrane trafficking and antigen processing significantly influences the human response to influenza vaccination. More broadly, we demonstrate that an integrative study design is an efficient alternative to existing methods for the identification of genes involved in complex traits.
eLife digest
Vaccines increase resistance to disease by priming the immune system to respond to specific viruses or microorganisms. By presenting a weakened (or dead) form of a pathogen, or its toxins or surface proteins, to the immune system, vaccines trigger the production of antibodies against the virus or microorganism. If a vaccinated individual then encounters the pathogen, their immune system should be able to recognize and destroy it. Many vaccines also include a secondary agent, known as an adjuvant, to further stimulate the immune response.
Influenza, an RNA virus commonly referred to as the ‘flu’, is an infectious disease that affects both birds and mammals. Seasonal epidemics occur each year affecting 2–7% of the population. According to the World Health Organization, influenza leads to nearly 5 million hospitalizations each year and causes up to half a million deaths. Vaccination is a primary strategy for the prevention of seasonal influenza, but responses to the vaccine vary markedly, partly because of variation in the genetic makeup or genotype of individuals. However, the details of how genes influence response to vaccination, and indeed susceptibility to influenza, remain unclear.
To investigate the genetic basis of variation in the immune response of healthy adults to the seasonal influenza vaccine, Franco et al. combined information about the genotypes of individuals with measurements of their gene transcription and antibody response to vaccination. They identified 20 genes that contributed to differential immune responses to the vaccine. Almost half of these encode proteins that are not specifically associated with the immune system, but have more general roles in processes such as membrane trafficking and intracellular transport.
Focusing on these genes may enable researchers to spot those individuals who are less likely to respond to a vaccine. It could also open up new avenues of research for vaccine development: rather than designing adjuvants that target known immune mechanisms, researchers should develop adjuvants that target the proteins encoded by these 20 genes.
PMCID: PMC3713456  PMID: 23878721
Complex-trait genetic; Vaccine; Human genetic; Integrative biology; Systems biology; eQTL; Human

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