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1.  Clinical Genetic Testing for Patients With Autism Spectrum Disorders 
Pediatrics  2010;125(4):e727-e735.
BACKGROUND
Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established.
PATIENTS AND METHODS
A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared.
RESULTS
Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%–2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%–0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%–21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%–8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changesin7.3%(51 of 697) and 5.3%(8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients.
CONCLUSIONS
CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.
doi:10.1542/peds.2009-1684
PMCID: PMC4247857  PMID: 20231187
array CGH; aCGH; autism spectrum disorder; ASD; language delay; microdeletion; microduplication; neuropsychiatric disorders
2.  Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis 
Frontiers in Genetics  2014;5:401.
Objective: We report the first pediatric specific Phenome-Wide Association Study (PheWAS) using electronic medical records (EMRs). Given the early success of PheWAS in adult populations, we investigated the feasibility of this approach in pediatric cohorts in which associations between a previously known genetic variant and a wide range of clinical or physiological traits were evaluated. Although computationally intensive, this approach has potential to reveal disease mechanistic relationships between a variant and a network of phenotypes.
Method: Data on 5049 samples of European ancestry were obtained from the EMRs of two large academic centers in five different genotyped cohorts. Recently, these samples have undergone whole genome imputation. After standard quality controls, removing missing data and outliers based on principal components analyses (PCA), 4268 samples were used for the PheWAS study. We scanned for associations between 2476 single-nucleotide polymorphisms (SNP) with available genotyping data from previously published GWAS studies and 539 EMR-derived phenotypes. The false discovery rate was calculated and, for any new PheWAS findings, a permutation approach (with up to 1,000,000 trials) was implemented.
Results: This PheWAS found a variety of common variants (MAF > 10%) with prior GWAS associations in our pediatric cohorts including Juvenile Rheumatoid Arthritis (JRA), Asthma, Autism and Pervasive Developmental Disorder (PDD) and Type 1 Diabetes with a false discovery rate < 0.05 and power of study above 80%. In addition, several new PheWAS findings were identified including a cluster of association near the NDFIP1 gene for mental retardation (best SNP rs10057309, p = 4.33 × 10−7, OR = 1.70, 95%CI = 1.38 − 2.09); association near PLCL1 gene for developmental delays and speech disorder [best SNP rs1595825, p = 1.13 × 10−8, OR = 0.65(0.57 − 0.76)]; a cluster of associations in the IL5-IL13 region with Eosinophilic Esophagitis (EoE) [best at rs12653750, p = 3.03 × 10−9, OR = 1.73 95%CI = (1.44 − 2.07)], previously implicated in asthma, allergy, and eosinophilia; and association of variants in GCKR and JAZF1 with allergic rhinitis in our pediatric cohorts [best SNP rs780093, p = 2.18 × 10−5, OR = 1.39, 95%CI = (1.19 − 1.61)], previously demonstrated in metabolic disease and diabetes in adults.
Conclusion: The PheWAS approach with re-mapping ICD-9 structured codes for our European-origin pediatric cohorts, as with the previous adult studies, finds many previously reported associations as well as presents the discovery of associations with potentially important clinical implications.
doi:10.3389/fgene.2014.00401
PMCID: PMC4235428  PMID: 25477900
PheWAS; ICD-9 code; genetic polymorphism
3.  Inheritance of Febrile Seizures in Sudden Unexplained Death in Toddlers 
Pediatric neurology  2012;46(4):235-239.
Sudden unexplained death in toddlers has been associated with febrile seizures, family history of febrile seizures, and hippocampal anomalies. We investigated the mode of inheritance for febrile seizures in these families. A three-generation pedigree was obtained from families enrolled in the San Diego Sudden Unexplained Death in Childhood Research Project, involving toddlers with sudden unexplained death, febrile seizures, and family history of febrile seizures. In our six cases, death was unwitnessed and related to sleep. The interval from last witnessed febrile seizure to death ranged from 3 weeks to 6 months. Hippocampal abnormalities were identified in one of three cases with available autopsy sections. Autosomal dominant inheritance of febrile seizures was observed in three families. A fourth demonstrated autosomal dominant inheritance with incomplete penetrance or variable expressivity. In two families, the maternal and paternal sides manifested febrile seizures. In this series, the major pattern of inheritance in toddlers with sudden unexplained death and febrile seizures was autosomal dominant. Future studies should develop markers (including genetic) to identify which patients with febrile seizures are at risk for sudden unexplained death in childhood, and to provide guidance for families and physicians.
doi:10.1016/j.pediatrneurol.2012.02.007
PMCID: PMC4009678  PMID: 22490769
4.  Recommendations for returning genomic incidental findings? We need to talk! 
The American College of Medical Genetics and Genomics recently issued recommendations for reporting incidental findings from clinical whole-genome sequencing and whole-exome sequencing. The recommendations call for evaluating a specific set of genes as part of all whole-genome sequencing/whole-exome sequencing and reporting all pathogenic variants irrespective of patient age. The genes are associated with highly penetrant disorders for which treatment or prevention is available. The effort to generate a list of genes with actionable findings is commendable, but the recommendations raise several concerns. They constitute a call for opportunistic screening, through intentional effort to identify pathogenic variants in specified genes unrelated to the clinical concern that prompted testing. Yet for most of the genes, we lack evidence about the predictive value of testing, genotype penetrance, spectrum of phenotypes, and efficacy of interventions in unselected populations. Furthermore, the recommendations do not allow patients to decline the additional findings, a position inconsistent with established norms. Finally, the recommendation to return adult-onset disease findings when children are tested is inconsistent with current professional consensus, including other policy statements of the American College of Medical Genetics and Genomics. Instead of premature practice recommendations, we call for robust dialogue among stakeholders to define a pathway to normatively sound, evidence-based guidelines.
doi:10.1038/gim.2013.113
PMCID: PMC3832423  PMID: 23907645
5.  Return of results in the genomic medicine projects of the eMERGE network 
The electronic Medical Records and Genomics (eMERGE) (Phase I) network was established in 2007 to further genomic discovery using biorepositories linked to the electronic health record (EHR). In Phase II, which began in 2011, genomic discovery efforts continue and in addition the network is investigating best practices for implementing genomic medicine, in particular, the return of genomic results in the EHR for use by physicians at point-of-care. To develop strategies for addressing the challenges of implementing genomic medicine in the clinical setting, the eMERGE network is conducting studies that return clinically-relevant genomic results to research participants and their health care providers. These genomic medicine pilot studies include returning individual genetic variants associated with disease susceptibility or drug response, as well as genetic risk scores for common “complex” disorders. Additionally, as part of a network-wide pharmacogenomics-related project, targeted resequencing of 84 pharmacogenes is being performed and select genotypes of pharmacogenetic relevance are being placed in the EHR to guide individualized drug therapy. Individual sites within the eMERGE network are exploring mechanisms to address incidental findings generated by resequencing of the 84 pharmacogenes. In this paper, we describe studies being conducted within the eMERGE network to develop best practices for integrating genomic findings into the EHR, and the challenges associated with such work.
doi:10.3389/fgene.2014.00050
PMCID: PMC3972474  PMID: 24723935
genomics; electronic health records; incidental findings; implementation; genetic counseling; next generation sequencing; pharmacogenetics
6.  An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge 
Brownstein, Catherine A | Beggs, Alan H | Homer, Nils | Merriman, Barry | Yu, Timothy W | Flannery, Katherine C | DeChene, Elizabeth T | Towne, Meghan C | Savage, Sarah K | Price, Emily N | Holm, Ingrid A | Luquette, Lovelace J | Lyon, Elaine | Majzoub, Joseph | Neupert, Peter | McCallie Jr, David | Szolovits, Peter | Willard, Huntington F | Mendelsohn, Nancy J | Temme, Renee | Finkel, Richard S | Yum, Sabrina W | Medne, Livija | Sunyaev, Shamil R | Adzhubey, Ivan | Cassa, Christopher A | de Bakker, Paul IW | Duzkale, Hatice | Dworzyński, Piotr | Fairbrother, William | Francioli, Laurent | Funke, Birgit H | Giovanni, Monica A | Handsaker, Robert E | Lage, Kasper | Lebo, Matthew S | Lek, Monkol | Leshchiner, Ignaty | MacArthur, Daniel G | McLaughlin, Heather M | Murray, Michael F | Pers, Tune H | Polak, Paz P | Raychaudhuri, Soumya | Rehm, Heidi L | Soemedi, Rachel | Stitziel, Nathan O | Vestecka, Sara | Supper, Jochen | Gugenmus, Claudia | Klocke, Bernward | Hahn, Alexander | Schubach, Max | Menzel, Mortiz | Biskup, Saskia | Freisinger, Peter | Deng, Mario | Braun, Martin | Perner, Sven | Smith, Richard JH | Andorf, Janeen L | Huang, Jian | Ryckman, Kelli | Sheffield, Val C | Stone, Edwin M | Bair, Thomas | Black-Ziegelbein, E Ann | Braun, Terry A | Darbro, Benjamin | DeLuca, Adam P | Kolbe, Diana L | Scheetz, Todd E | Shearer, Aiden E | Sompallae, Rama | Wang, Kai | Bassuk, Alexander G | Edens, Erik | Mathews, Katherine | Moore, Steven A | Shchelochkov, Oleg A | Trapane, Pamela | Bossler, Aaron | Campbell, Colleen A | Heusel, Jonathan W | Kwitek, Anne | Maga, Tara | Panzer, Karin | Wassink, Thomas | Van Daele, Douglas | Azaiez, Hela | Booth, Kevin | Meyer, Nic | Segal, Michael M | Williams, Marc S | Tromp, Gerard | White, Peter | Corsmeier, Donald | Fitzgerald-Butt, Sara | Herman, Gail | Lamb-Thrush, Devon | McBride, Kim L | Newsom, David | Pierson, Christopher R | Rakowsky, Alexander T | Maver, Aleš | Lovrečić, Luca | Palandačić, Anja | Peterlin, Borut | Torkamani, Ali | Wedell, Anna | Huss, Mikael | Alexeyenko, Andrey | Lindvall, Jessica M | Magnusson, Måns | Nilsson, Daniel | Stranneheim, Henrik | Taylan, Fulya | Gilissen, Christian | Hoischen, Alexander | van Bon, Bregje | Yntema, Helger | Nelen, Marcel | Zhang, Weidong | Sager, Jason | Zhang, Lu | Blair, Kathryn | Kural, Deniz | Cariaso, Michael | Lennon, Greg G | Javed, Asif | Agrawal, Saloni | Ng, Pauline C | Sandhu, Komal S | Krishna, Shuba | Veeramachaneni, Vamsi | Isakov, Ofer | Halperin, Eran | Friedman, Eitan | Shomron, Noam | Glusman, Gustavo | Roach, Jared C | Caballero, Juan | Cox, Hannah C | Mauldin, Denise | Ament, Seth A | Rowen, Lee | Richards, Daniel R | Lucas, F Anthony San | Gonzalez-Garay, Manuel L | Caskey, C Thomas | Bai, Yu | Huang, Ying | Fang, Fang | Zhang, Yan | Wang, Zhengyuan | Barrera, Jorge | Garcia-Lobo, Juan M | González-Lamuño, Domingo | Llorca, Javier | Rodriguez, Maria C | Varela, Ignacio | Reese, Martin G | De La Vega, Francisco M | Kiruluta, Edward | Cargill, Michele | Hart, Reece K | Sorenson, Jon M | Lyon, Gholson J | Stevenson, David A | Bray, Bruce E | Moore, Barry M | Eilbeck, Karen | Yandell, Mark | Zhao, Hongyu | Hou, Lin | Chen, Xiaowei | Yan, Xiting | Chen, Mengjie | Li, Cong | Yang, Can | Gunel, Murat | Li, Peining | Kong, Yong | Alexander, Austin C | Albertyn, Zayed I | Boycott, Kym M | Bulman, Dennis E | Gordon, Paul MK | Innes, A Micheil | Knoppers, Bartha M | Majewski, Jacek | Marshall, Christian R | Parboosingh, Jillian S | Sawyer, Sarah L | Samuels, Mark E | Schwartzentruber, Jeremy | Kohane, Isaac S | Margulies, David M
Genome Biology  2014;15(3):R53.
Background
There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.
Results
A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization.
Conclusions
The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
doi:10.1186/gb-2014-15-3-r53
PMCID: PMC4073084  PMID: 24667040
8.  EMR-linked GWAS study: investigation of variation landscape of loci for body mass index in children 
Frontiers in Genetics  2013;4:268.
Common variations at the loci harboring the fat mass and obesity gene (FTO), MC4R, and TMEM18 are consistently reported as being associated with obesity and body mass index (BMI) especially in adult population. In order to confirm this effect in pediatric population five European ancestry cohorts from pediatric eMERGE-II network (CCHMC-BCH) were evaluated.
Method: Data on 5049 samples of European ancestry were obtained from the Electronic Medical Records (EMRs) of two large academic centers in five different genotyped cohorts. For all available samples, gender, age, height, and weight were collected and BMI was calculated. To account for age and sex differences in BMI, BMI z-scores were generated using 2000 Centers of Disease Control and Prevention (CDC) growth charts. A Genome-wide association study (GWAS) was performed with BMI z-score. After removing missing data and outliers based on principal components (PC) analyses, 2860 samples were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and BMI was tested using linear regression adjusting for age, gender, and PC by cohort. The effects of SNPs were modeled assuming additive, recessive, and dominant effects of the minor allele. Meta-analysis was conducted using a weighted z-score approach.
Results: The mean age of subjects was 9.8 years (range 2–19). The proportion of male subjects was 56%. In these cohorts, 14% of samples had a BMI ≥95 and 28 ≥ 85%. Meta analyses produced a signal at 16q12 genomic region with the best result of p = 1.43 × 10-7 [p(rec) = 7.34 × 10-8) for the SNP rs8050136 at the first intron of FTO gene (z = 5.26) and with no heterogeneity between cohorts (p = 0.77). Under a recessive model, another published SNP at this locus, rs1421085, generates the best result [z = 5.782, p(rec) = 8.21 × 10-9]. Imputation in this region using dense 1000-Genome and Hapmap CEU samples revealed 71 SNPs with p < 10-6, all at the first intron of FTO locus. When hetero-geneity was permitted between cohorts, signals were also obtained in other previously identified loci, including MC4R (rs12964056, p = 6.87 × 10-7, z = -4.98), cholecystokinin CCK (rs8192472, p = 1.33 × 10-6, z = -4.85), Interleukin 15 (rs2099884, p = 1.27 × 10-5, z = 4.34), low density lipoprotein receptor-related protein 1B [LRP1B (rs7583748, p = 0.00013, z = -3.81)] and near transmembrane protein 18 (TMEM18) (rs7561317, p = 0.001, z = -3.17). We also detected a novel locus at chromosome 3 at COL6A5 [best SNP = rs1542829, minor allele frequency (MAF) of 5% p = 4.35 × 10-9, z = 5.89].
Conclusion: An EMR linked cohort study demonstrates that the BMI-Z measurements can be successfully extracted and linked to genomic data with meaningful confirmatory results. We verified the high prevalence of childhood rate of overweight and obesity in our cohort (28%). In addition, our data indicate that genetic variants in the first intron of FTO, a known adult genetic risk factor for BMI, are also robustly associated with BMI in pediatric population.
doi:10.3389/fgene.2013.00268
PMCID: PMC3847941  PMID: 24348519
BMI; obesity; polymorphism; GWAS
9.  The Beliefs, Motivations, and Expectations of Parents Who Have Enrolled Their Children in a Genetic Biorepository 
Purpose
Little is known about parental attitudes toward return of individual research results (IRRs) in pediatric genomic research. The aim of this study was to understand the views of the parents who enrolled their children in a genomic repository in which IRRs will be returned.
Methods
We conducted focus groups with parents of children with developmental disorders enrolled in the Gene Partnership (GP), a genomic research repository that offers to return IRRs, to learn about their understanding of the GP, motivations for enrolling their children, and expectations regarding the return of IRRs.
Results
Parents hoped to receive IRRs that would help them better understand their children’s condition(s). They understood that this outcome was unlikely, but hoped that their children’s participation in the GP would contribute to scientific knowledge. Most parents wanted to receive all IRRs about their child, even for diseases that were severe and untreatable, citing reasons of personal utility. Parents preferred electronic delivery of the results and wanted to designate their preferences regarding what information they would receive.
Conclusion
It is important for researchers to understand participant expectations in enrolling in a research repository that offers to disclose children’s IRRs in order to effectively communicate the implications to parents during the consenting process.
doi:10.1038/gim.2011.25
PMCID: PMC3763713  PMID: 22241099
biorepository research; individual research results; parent perspectives; pediatric biobank; pediatric genetic research; returning research results
10.  Multiple juvenile idiopathic arthritis subtypes demonstrate pro-inflammatory IgG glycosylation 
Arthritis and rheumatism  2012;64(9):3025-3033.
OBJECTIVES
Rheumatoid arthritis is associated with an excess of hypogalactosylated (G0) IgG that is considered relatively pro-inflammatory. Assessment of this association in juvenile idiopathic arthritis (JIA) is complicated by age-dependent IgG glycan variation. We undertook the first large-scale survey of IgG glycans in normal children and in patients with JIA, with a focus on early childhood, the time of peak JIA incidence.
METHODS
IgG glycans from healthy children and DMARD-naïve JIA patients were characterized using high-performance liquid chromatography (HPLC). Pro-inflammatory G0 glycans were quantitated with reference to monogalactosylated (G1) species. Associations were sought between G0/G1 and disease characteristics.
RESULTS
Among healthy children aged 9 months-16 years (n=165), G0/G1 was highly age-dependent, peaking in children <3 years old at 1.19 and declining to a nadir of 0.83 after age 10 years (Spearman ρ=0.60, p<0.0001). In patients with JIA (n=141), G0/G1 was elevated compared with controls (G0/G1 1.32 vs. 1.02, p<0.0001). Corrected for age, G0/G1 was abnormally high in all JIA subtypes (enthesitis-related arthritis not assessed), most strikingly in systemic JIA. Glycosylation aberrancy was comparable in patients with or without ANA and in both early- and late-onset disease, and exhibited at most a weak correlation with inflammatory markers.
CONCLUSIONS
IgG glycosylation is skewed toward pro-inflammatory G0 variants in healthy children, in particular during the first few years of life. This deviation is exaggerated in patients with JIA. The role for IgG glycan variation in immune function in children, including the predilection of JIA for early childhood, remains to be defined.
doi:10.1002/art.34507
PMCID: PMC3429730  PMID: 22549726
11.  Characteristics and Predictive Value of Blood Transcriptome Signature in Males with Autism Spectrum Disorders 
PLoS ONE  2012;7(12):e49475.
Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases. Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62–0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65–0.82), but not for female samples (AUC 0.51, 95% CI 0.36–0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58–0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified.
doi:10.1371/journal.pone.0049475
PMCID: PMC3515554  PMID: 23227143
12.  A CLINICIAN'S GUIDE TO X-LINKED HYPOPHOSPHATEMIA 
X-linked hypophosphatemia (XLH) is the prototypic disorder of renal phosphate wasting, and the most common form of heritable rickets. Physicians, patients, and XLH support groups have all expressed concerns about the dearth of information about this disease and the lack of treatment guidelines which frequently lead to missed diagnoses or mismanagement. This perspective addresses the recommendation by conferees for the dissemination of concise and accessible treatment guidelines for clinicians arising from the “Advances in Rare Bone Diseases Scientific Conference,” held at the National Institutes of Health in October 2008. We briefly review the clinical and pathophysiologic features of the disorder, and offer this guide in response to the conference recommendation, base on our collective accumulated experience in the management of this complex disorder.
doi:10.1002/jbmr.340
PMCID: PMC3157040  PMID: 21538511
Phosphate; FGF23; PHEX; rickets; osteomalacia
13.  Lack of Association of the Serotonin Transporter Polymorphism With the Sudden Infant Death Syndrome in the San Diego Dataset 
Pediatric research  2010;68(5):409-413.
Dysfunction of medullary serotonin (5-HT)-mediated respiratory and autonomic function is postulated to underlie the pathogenesis of the majority of sudden infant death syndrome (SIDS) cases. Several studies have reported an increased frequency of the LL genotype and L allele of the 5-HT transporter (5-HTT) gene promoter polymorphism (5-HTTLPR), which is associated with increased transcriptional activity and 5-HT transport in vitro, in SIDS cases compared with controls. These findings raise the possibility that this polymorphism contributes to or exacerbates existing medullary 5-HT dysfunction in SIDS. In this study, we tested the hypothesis that the frequency of LL genotype and L allele are higher in 179 SIDS cases compared with 139 controls of multiple ethnicities in the San Diego SIDS Dataset. We observed no significant association of genotype or allele with SIDS cases either in the total cohort or on stratification for ethnicity. These observations do not support previous findings that the L allele and/or LL genotype of the 5-HTTLPR are associated with SIDS.
doi:10.1203/PDR.0b013e3181f2edf0
PMCID: PMC3242414  PMID: 20661167
14.  Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome 
PLoS Genetics  2011;7(4):e1002050.
Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.
Author Summary
Children with cartilage tumor syndromes form multiple tumors of cartilage next to joints. These tumors can occur inside the bones, as with Ollier disease and Maffuci syndrome, or on the surface of bones, as in the Multiple Osteochondroma syndrome (MO). In a hybrid syndrome, called metachondromatosis (MC), patients develop tumors both on and within bones. Only the genes causing MO are known. Since MC is inherited, we studied genetic markers in an affected family and found a region of the genome, encompassing 100 genes, always passed on to affected members. Using a recently developed method, we captured and sequenced all 100 genes in multiple families and found mutations in one gene, PTPN11, in 11 of 17 families. Patients with MC have one mutant copy of PTPN11 from their affected parent and one normal copy from their unaffected parent in all cells. We found that the normal copy is additionally lost in cartilage cells that form tumors, giving rise to cells without PTPN11. Mutations in PTPN11 were not found in other cartilage tumor syndromes, including Ollier disease and Maffucci syndrome. We are currently working to understand how loss of PTPN11 in cartilage cells causes tumors to form.
doi:10.1371/journal.pgen.1002050
PMCID: PMC3077396  PMID: 21533187
15.  The Serotonin-Related FEV Gene Variant in the Sudden Infant Death Syndrome is a Common Polymorphism in the African–American Population 
Pediatric research  2009;66(6):631-635.
An important subset of the sudden infant death syndrome (SIDS) is associated with multiple serotonergic (5-HT) abnormalities in regions of the medulla oblongata. The mouse ortholog of the fifth Ewing variant gene (FEV) is critical for 5-HT neuronal development. A putatively rare intronic variant [IVS2-191_190insA, here referred to as c.128-(191_192)dupA] has been reported as a SIDS-associated mutation in an African-American population. We tested this association in an independent dataset: 137 autopsied cases (78 SIDS, 59 controls) and an additional 296 control DNA samples from Coriell Cell Repositories. In addition to the c.128-(191_192)dupA variant, we observed an associated single base deletion [c.128-(301–306)delG] in a subset of the samples. Neither of the two FEV variants showed significant association with SIDS in either the African-American subgroup or the overall cohort. Although we found a significant association of c.128-(191_192)dupA with SIDS when San Diego Hispanic SIDS cases were compared with San Diego Hispanic controls plus Mexican controls (p=0.04); this became non-significant after multiple testing correction. Among Coriell controls, 33/99 (33%) African-American and 0/197 (0%) of the remaining controls carry the polymorphism (c.128-(191_192)dupA). The polymorphism appears to be a common, likely non-pathogenic, variant in the African-American population.
doi:10.1203/PDR.0b013e3181bd5a31
PMCID: PMC2802663  PMID: 19707175
16.  Bone Disease in Thalassemia: A Frequent and Still Unresolved Problem 
Adults with β thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, ≥6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1–75 yr), were studied. Spine and femur BMD Z-scores < −2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.
doi:10.1359/jbmr.080505
PMCID: PMC3276604  PMID: 18505376
DXA; BMD; fractures; vertebral morphometry; thalassemia

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