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1.  CANOES: detecting rare copy number variants from whole exome sequencing data 
Nucleic Acids Research  2014;42(12):e97.
We present CANOES, an algorithm for the detection of rare copy number variants from exome sequencing data. CANOES models read counts using a negative binomial distribution and estimates variance of the read counts using a regression-based approach based on selected reference samples in a given dataset. We test CANOES on a family-based exome sequencing dataset, and show that its sensitivity and specificity is comparable to that of XHMM. Moreover, the method is complementary to Gaussian approximation-based methods (e.g. XHMM or CoNIFER). When CANOES is used in combination with these methods, it will be possible to produce high accuracy calls, as demonstrated by a much reduced and more realistic de novo rate in results from trio data.
doi:10.1093/nar/gku345
PMCID: PMC4081054  PMID: 24771342
2.  Variants in GATA4 Are a Rare Cause of Familial and Sporadic Congenital Diaphragmatic Hernia 
Human genetics  2012;132(3):285-292.
Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm, occurring as either an isolated defect or in association with other anomalies. Genetic factors including aneuploidies and copy number variants are important in the pathogenesis of many cases of CDH, but few single genes have been definitively implicated in human CDH. In this study, we used whole exome sequencing (WES) to identify a paternally inherited novel missense GATA4 variant (c. 754C>T, p. R252W) in a familial case of CDH with incomplete penetrance. Phenotypic characterization of the family included magnetic resonance imaging (MRI) of the chest and abdomen demonstrating asymptomatic defects in the diaphragm in the two “unaffected” missense variant carriers. Screening 96 additional CDH patients identified a de novo heterozygous GATA4 variant (c.848G>A; p.R283H) in a non-isolated CDH patient. In summary, GATA4 is implicated in both familial and sporadic CDH, and our data suggests that WES may be a powerful tool to discover rare variants for CDH.
doi:10.1007/s00439-012-1249-0
PMCID: PMC3570587  PMID: 23138528
Congenital diaphragmatic Hernia (CDH); whole exome sequencing (WES); incomplete penetrance; missense variant; GATA4
3.  Researchers’ views on return of incidental genomic research results: qualitative and quantitative findings 
Purpose
Comprehensive genomic analysis including exome and genome sequencing is increasingly being utilized in research studies, leading to the generation of incidental genetic findings. It is unclear how researchers plan to deal with incidental genetic findings.
Methods
We conducted a survey of the practices and attitudes of 234 members of the US genetic research community and performed qualitative semistructured interviews with 28 genomic researchers to understand their views and experiences with incidental genetic research findings.
Results
We found that 12% of the researchers had returned incidental genetic findings, and an additional 28% planned to do so. A large majority of researchers (95%) believe that incidental findings for highly penetrant disorders with immediate medical implications should be offered to research participants. However, there was no consensus on returning incidental results for other conditions varying in penetrance and medical actionability. Researchers raised concerns that the return of incidental findings would impose significant burdens on research and could potentially have deleterious effects on research participants if not performed well. Researchers identified assistance needed to enable effective, accurate return of incidental findings.
Conclusion
The majority of the researchers believe that research participants should have the option to receive at least some incidental genetic research results.
doi:10.1038/gim.2013.87
PMCID: PMC3823712  PMID: 23807616
genomic results; incidental findings; return of results; secondary findings; whole-exome sequencing
4.  Opposing Brain Differences in 16p11.2 Deletion and Duplication Carriers 
The Journal of Neuroscience  2014;34(34):11199-11211.
Deletions and duplications of the recurrent ∼600 kb chromosomal BP4–BP5 region of 16p11.2 are associated with a broad variety of neurodevelopmental outcomes including autism spectrum disorder. A clue to the pathogenesis of the copy number variant (CNV)'s effect on the brain is that the deletion is associated with a head size increase, whereas the duplication is associated with a decrease. Here we analyzed brain structure in a clinically ascertained group of human deletion (N = 25) and duplication (N = 17) carriers from the Simons Variation in Individuals Project compared with age-matched controls (N = 29 and 33, respectively). Multiple brain measures showed increased size in deletion carriers and reduced size in duplication carriers. The effects spanned global measures of intracranial volume, brain size, compartmental measures of gray matter and white matter, subcortical structures, and the cerebellum. Quantitatively, the largest effect was on the thalamus, but the collective results suggest a pervasive rather than a selective effect on the brain. Detailed analysis of cortical gray matter revealed that cortical surface area displays a strong dose-dependent effect of CNV (deletion > control > duplication), whereas average cortical thickness is less affected. These results suggest that the CNV may exert its opposing influences through mechanisms that influence early stages of embryonic brain development.
doi:10.1523/JNEUROSCI.1366-14.2014
PMCID: PMC4138332  PMID: 25143601
16p11.2; ASD; CNV; copy number variation; morphometry; structural MRI
5.  De novo copy number variants are associated with congenital diaphragmatic hernia 
Journal of medical genetics  2012;49(10):650-659.
Background
Congenital diaphragmatic hernia (CDH) is a common birth defect with significant morbidity and mortality. Although the etiology of CDH remains poorly understood, studies from animal models and patients with CDH suggest that genetic factors play an important role in the development of CDH. Chromosomal anomalies have been reported in CDH.
Methods
In this study, the authors investigate the frequency of chromosomal anomalies and copy number variants in 256 parent-child trios of CDH using clinical conventional cytogenetic and microarray analysis. The authors also selected a set of CDH related training genes to prioritize the genes in those segmental aneuploidies and identified the genes and gene sets that may contribute to the etiology of CDH.
Results
The authors identified chromosomal anomalies in 16 patients (6.3 %) of the series including 3 aneuploidies, 2 unbalanced translocation, and 11 patients with de novo CNVs ranging in size from 95 kb to 104.6 Mb. The authors prioritized the genes in the CNV segments and identified KCNA2, LMNA, CACNA1S, MYOG, HLX, LBR, AGT, GATA4, SOX7, HYLS1, FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, HOMER2, BNC1, BID, and TBX1 as genes that may be involved in diaphragm development. Gene enrichment analysis identified the most relevant gene ontology (GO) categories as those involved in tissue development (p=4.4×10−11) or regulation of multicellular organismal processes (p=2.8×10−10) and “receptor binding” (p = 8.7×10−14) and “DNA binding transcription factor activity” (p= 4.4×10−10).
Conclusions
Our findings support the role of chromosomal anomalies in CDH and provide a set of candidate genes including FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, SOX7,BNC1, BID, and TBX1 for further analysis in CDH.
doi:10.1136/jmedgenet-2012-101135
PMCID: PMC3696999  PMID: 23054247
Congenital diaphragmatic hernia (CDH); copy number variant (CNV); chromosomal anomalies; gene priority; gene enrichment
6.  Mutation in SNAP25 as a novel genetic cause of epilepsy and intellectual disability 
Rare Diseases  2013;1:e26314.
Whole exome sequencing using a parent-child trio design to identify de novo mutations provides an efficient method to identify novel genes for rare diseases with low reproductive fitness that are difficult to study by more classical genetic methods of linkage analysis. We describe a 15 y old female with severe static encephalopathy, intellectual disability, and generalized epilepsy. After extensive metabolic and genetic testing, whole exome sequencing identified a novel de novo variant in Synaptosomal-associated protein-25 (SNAP25), c.142G > T p.Phe48Val alteration. This variant is predicted to be damaging by all prediction algorithms. SNAP25 is part of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complex which is involved in exocytotic release of neurotransmitters. Genetic alterations in Snap25 in animal models can cause anxiety-related behavior, ataxia and seizures. We suggest that SNAP25 mutations in humans are a novel genetic cause of intellectual disability and epilepsy.
doi:10.4161/rdis.26314
PMCID: PMC3932847  PMID: 25003006
SNAP25; intellectual disability; epilepsy; whole exome sequencing; novel mutation
7.  A human de novo mutation in MYH10 phenocopies the loss of function mutation in mice 
Rare Diseases  2013;1:e26144.
We used whole exome sequence analysis to investigate a possible genetic etiology for a patient with the phenotype of intrauterine growth restriction, microcephaly, developmental delay, failure to thrive, congenital bilateral hip dysplasia, cerebral and cerebellar atrophy, hydrocephalus, and congenital diaphragmatic hernia (CDH).
Whole exome sequencing identified a novel de novo c.2722G > T (p.E908X) mutation in the Myosin Heavy Chain 10 gene (MYH10) which encodes for non-muscle heavy chain II B (NMHC IIB). Mutations in MYH10 have not been previously described in association with human disease. The E908X mutation is located in the coiled-coil region of the protein and is expected to delete the tail domain and disrupt filament assembly.
Nonmuscle myosin IIs (NM IIs) are a group of ubiquitously expressed proteins, and NM II B is specifically enriched in neuronal tissue and is thought to be important in neuronal migration. It is also expressed in cardiac myocytes along with NM IIC.
Homozygous NMHC II B-/B- mouse knockouts die by embryonic day (E)14.5 with severe cardiac defects (membranous ventricular septal defect and cardiac outflow tract abnormalities) and neurodevelopmental disorders (progressive hydrocephalus and neuronal migrational abnormalities).
A heterozygous MYH10 loss of function mutation produces a severe neurologic phenotype and CDH but no apparent cardiac phenotype and suggests that MYH10 may represent a novel gene for brain malformations and/or CDH.
doi:10.4161/rdis.26144
PMCID: PMC3927488  PMID: 25003005
whole exome sequencing; MYH10; intellectual disability; microcephaly; NMHC II B
8.  Quantitative Analysis of Copy Number Variants Based on Real-Time LightCycler PCR 
Quantitative real-time PCR is PCR visualized in real time by the use of fluorescent or intercalating dyes used to measure gene expression or gene quantification including including contiguous gene deletions or duplications. A simple method is described to quantify DNA copy number from human samples.
doi:10.1002/0471142905.hg0721s80
PMCID: PMC3949243  PMID: 24510682
qPCR; CNV; copy number analysis
9.  Whole Exome Sequencing to Identify a Novel Gene (Caveolin-1) Associated with Human Pulmonary Arterial Hypertension 
Background
Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to TGF beta signaling, including bone morphogenetic protein receptor type 2 (BMPR2), activin receptor-like kinase 1 (ALK1), endoglin (ENG), and mothers against decapentaplegic 9 (SMAD9). Approximately 25% of heritable cases lack identifiable mutations in any of these genes.
Methods and Results
We used whole exome sequencing to study a three generation family with multiple affected family members with PAH but no identifiable TGF beta mutation. We identified a frameshift mutation in Caveolin-1 (CAV1), which encodes a membrane protein of caveolae abundant in the endothelium and other cells of the lung. An independent de novo frameshift mutation was identified in a child with idiopathic PAH. Western blot analysis demonstrated a reduction in caveolin-1 protein, while lung tissue immunostaining studies demonstrated a reduction in normal caveolin-1 density within the endothelial cell layer of small arteries.
Conclusions
Our study represents successful elucidation of a dominant Mendelian disorder using whole exome sequencing. Mutations in CAV1 are associated in rare cases with PAH. This may have important implications for pulmonary vascular biology as well as PAH-directed therapeutic development.
doi:10.1161/CIRCGENETICS.111.961888
PMCID: PMC3380156  PMID: 22474227
bioinfomatics genes; genetics; BMPR2; caveolae; pulmonary hypertension
10.  An Overview of Mongenic and Syndromic Obesities in Humans 
Pediatric blood & cancer  2011;58(1):122-128.
Obesity is increasing in prevalence in the United States with over 65% of adults considered overweight and 16% of children with BMI > 95 percentile. The heritability of obesity is estimated between 40 and 70%, but the genetics of obesity for most individuals are complex and involve the interaction of multiple genes and environment. There are however several syndromic and non-syndromic forms of obesity that are monogenic and oligogenic that provide insight into the underlying molecular control of food intake and the neural networks that control ingestive behavior and satiety to regulate body weight and which may interact with treatment exposures to produce or exacerbate obesity in childhood cancer survivors.
doi:10.1002/pbc.23372
PMCID: PMC3215910  PMID: 21994130
leptin; leptin receceptor; melanocortin 4 receptor; Prader Willi syndrome; Bardet-Biedl syndrome; Alstrom syndrome; 16p11.2 deletion
11.  Defining a comprehensive verotype using electronic health records for personalized medicine 
The burgeoning adoption of electronic health records (EHR) introduces a golden opportunity for studying individual manifestations of myriad diseases, which is called ‘EHR phenotyping’. In this paper, we break down this concept by: relating it to phenotype definitions from Johannsen; comparing it to cohort identification and disease subtyping; introducing a new concept called ‘verotype’ (Latin: vere = true, actually) to represent the ‘true’ population of similar patients for treatment purposes through the integration of genotype, phenotype, and disease subtype (eg, specific glucose value pattern in patients with diabetes) information; analyzing the value of the ‘verotype’ concept for personalized medicine; and outlining the potential for using network-based approaches to reverse engineer clinical disease subtypes.
doi:10.1136/amiajnl-2013-001932
PMCID: PMC3861934  PMID: 24001516
Electronic Health Records; Phenotype; Genotype; Genetics
12.  Genetic Association Analysis of 30 Genes Related to Obesity in a European American Population 
Objective
Obesity, which is frequently associated with diabetes, hypertension, and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI).
Methods
We re-analyzed 355 common genetic variants of 30 candidate genes in 7 molecular pathways related to obesity in 1,982 unrelated European Americans from the New York Health Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates including age, age2, gender, and diabetes status. The single nucleotide polymorphisms (SNPs) were modeled as additive effects.
Results
With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: GHRL (rs35683), AGRP (rs5030980), CPE (rs1946816 and rs4481204), GLP1R (rs2268641), HTR2A (rs912127), NPY5R (Y5R1c52), SOCS3 (rs4969170), and STAT3 (rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant.
Conclusion
Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3, and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake and thus these associations are mechanistically plausible in this context.
doi:10.1038/ijo.2013.140
PMCID: PMC3909018  PMID: 23900445
Obesity; genetic association; single nucleotide polymorphism (SNP); Bayesian hierarchical generalized linear model (BhGLM)
13.  Developmental outcomes of children with congenital diaphragmatic hernia: a multicenter prospective study 
Journal of pediatric surgery  2013;48(10):10.1016/j.jpedsurg.2013.02.041.
Purpose
To determine developmental outcomes and associated factors in patients with congenital diaphragmatic hernia (CDH) at two years of age.
Methods
This is a multicenter prospective study of a CDH birth cohort. Clinical and socioeconomic data were collected. Bayley Scales of Infant Development (BSID-III) and Vineland Adaptive Behavior Scales (VABS-II) were performed at two years of age.
Results
BSID-III and VABS-II assessments were completed on 48 and 49 children, respectively. The BSID-III mean cognitive, language, and motor scores were significantly below the norm mean with average scores of 93 +/− 15, 95 +/−16, and 95 +/− 11. Ten percent (5/47) scored more than two standard deviations below the norm on one or more domains. VABS-II scores were similar to BSID-III scores with mean communication, daily living skills, social, motor, adaptive behavior scores of 97 +/−14, 94+/−16, 93 +/− 13, 97+/− 10, and 94 +/− 14. For the BSID-III, supplemental oxygen at 28 days, a prenatal diagnosis, need for extracorporeal membrane oxygenation (ECMO) and exclusive tube feeds at time of discharge were associated with lower scores. At two years of age, history of hospital readmission and need for tube feeds were associated with lower scores. Lower socioeconomic status correlated with lower developmental scores when adjusted for significant health factors.
Conclusion
CDH patients on average have lower developmental scores at two years of age compared to the norm. A need for ECMO, oxygen at 28 days of life, ongoing health issues and lower socioeconomic status are factors associated with developmental delays.
doi:10.1016/j.jpedsurg.2013.02.041
PMCID: PMC3884579  PMID: 24094947
congenital diaphragmatic hernia; neurodevelopment; Hollingshead; socioeconomic status
14.  The Impact of CNVs on Outcomes for Infants with Single Ventricle Heart Defects 
Background
Human genomes harbor copy number variants (CNVs), regions of DNA gains or losses. While pathogenic CNVs are associated with congenital heart disease (CHD), their impact on clinical outcomes is unknown. This study sought to determine whether pathogenic CNVs among infants with single ventricle (SV) physiology were associated with inferior neurocognitive and somatic growth outcomes.
Methods and Results
Genomic DNAs from 223 subjects of two National Heart, Lung, and Blood Institute-sponsored randomized clinical trials with infants with SV CHD and 270 controls from The Cancer Genome Atlas project were analyzed for rare CNVs >300 kb using array comparative genomic hybridization. Neurocognitive and growth outcomes at 14 months from the CHD trials were compared among subjects with and without pathogenic CNVs. Putatively pathogenic CNVs, comprising 25 duplications and 6 deletions, had a prevalence of 13.9%, significantly greater than the 4.4% rate of such CNVs among controls. CNVs associated with genomic disorders were found in 13 cases but no control. Several CNVs likely to be causative of SV CHD were observed, including aberrations altering the dosage of GATA4, MYH11, and GJA5. Subjects with pathogenic CNVs had worse linear growth, and those with CNVs associated with known genomic disorders had the poorest neurocognitive and growth outcomes. A minority of children with pathogenic CNVs were noted to be dysmorphic on clinical genetics examination.
Conclusions
Pathogenic CNVs appear to contribute to the etiology of SV forms of CHD in at least 10% of cases, are clinically subtle but adversely affect outcomes in children harboring them.
doi:10.1161/CIRCGENETICS.113.000189
PMCID: PMC3987966  PMID: 24021551
copy number variant; congenital cardiac defect; outcome; hypoplastic left heart syndrome
15.  Views of Preimplantation Genetic Diagnosis (PGD) among Psychiatrists and Neurologists 
Objective
As prenatal genetic testing (GT) and Preimplantation Genetic Diagnosis (PGD) use increase, providers in many specialties may play roles in patient discussions and referrals. Hence, we examined key aspects of neurologists’ and psychiatrists’ views and approaches.
Study Design
We surveyed attitudes and practices among 163 neurologists and 372 psychiatrists.
Results
24.9% of neurologists and 31.9% of psychiatrists had discussed prenatal GT with patients, but 95.3% didn’t feel comfortable discussing PGD; only 2.9% discussed it; and only 1.8% had patients ask about PGD. Most would refer for PGD for Huntington’s disease (HD) and Tay-Sachs, fewer for Cystic Fibrosis (CF), and fewer still for autism, Alzheimer’s (AD), or gender selection for family balancing; in each of these cases, psychiatrists > neurologists. Providers who’d refer for PGD for HD, CF, or gender selection differed from others in proportions of patients with insurance, were more likely to have undergone a GT themselves, and be concerned about discrimination.
Conclusions
These data, the first to examine how neurologists and psychiatrists view PGD, suggest they don’t feel comfortable discussing PGD, but have strong views about its use. Potential PGD use is associated with concerns about discrimination, and less experience with GT. These data highlight needs for enhancing education about these technologies among various providers.
PMCID: PMC4129544  PMID: 25098029
doctor-patient communication; ethics; assisted reproductive technology; obstetrics/gynecology; eugenics
16.  Analysis of 30 Genes (355 SNPS) Related to Energy Homeostasis for Association with Adiposity in European-American and Yup'ik Eskimo Populations 
Human Heredity  2008;67(3):193-205.
Objective
Human adiposity is highly heritable, but few of the genes that predispose to obesity in most humans are known. We tested candidate genes in pathways related to food intake and energy expenditure for association with measures of adiposity.
Methods
We studied 355 genetic variants in 30 candidate genes in 7 molecular pathways related to obesity in two groups of adult subjects: 1,982 unrelated European Americans living in the New York metropolitan area drawn from the extremes of their body mass index (BMI) distribution and 593 related Yup'ik Eskimos living in rural Alaska characterized for BMI, body composition, waist circumference, and skin fold thicknesses. Data were analyzed by using a mixed model in conjunction with a false discovery rate (FDR) procedure to correct for multiple testing.
Results
After correcting for multiple testing, two single nucleotide polymorphisms (SNPs) in Ghrelin (GHRL) (rs35682 and rs35683) were associated with BMI in the New York European Americans. This association was not replicated in the Yup'ik participants. There was no evidence for gene × gene interactions among genes within the same molecular pathway after adjusting for multiple testing via FDR control procedure.
Conclusion
Genetic variation in GHRL may have a modest impact on BMI in European Americans.
doi:10.1159/000181158
PMCID: PMC2715950  PMID: 19077438
Obesity; Body composition; Body mass index; Candidate gene; Ghrelin
17.  Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families† 
Prenatal diagnosis  2009;29(6):560-569.
Objective
Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of α-dystroglycan (α-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS.
Method
We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis.
Results
We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults.
Conclusion
These data suggest that the c.1167insA FKTN mutation described by us is a founder mutation that can be used to target diagnostic testing and carrier screening in the Ashkenazi Jewish population.
doi:10.1002/pd.2238
PMCID: PMC2735827  PMID: 19266496
genetic screening; muscle-eye-brain disease
18.  Analysis of 30 Genes (355 SNPS) Related to Energy Homeostasis for Association with Adiposity in European-American and Yup’ik Eskimo Populations 
Human heredity  2008;67(3):193-205.
Objective
Human adiposity is highly heritable, but few of the genes that predispose to obesity in most humans are known. We tested candidate genes in pathways related to food intake and energy expenditure for association with measures of adiposity.
Methods
We studied 355 genetic variants in 30 candidate genes in 7 molecular pathways related to obesity in two groups of adult subjects: 1,982 unrelated European Americans living in the New York metropolitan area drawn from the extremes of their body mass index (BMI) distribution and 593 related Yup’ik Eskimos living in rural Alaska characterized for BMI, body composition, waist circumference, and skin fold thicknesses. Data were analyzed by using a mixed model in conjunction with a false discovery rate (FDR) procedure to correct for multiple testing.
Results
After correcting for multiple testing, two single nucleotide polymorphisms (SNPs) in Ghrelin (GHRL)(rs35682 and rs35683) were associated with BMI in the New York European Americans. This association was not replicated in the Yup’ik participants. There was no evidence for gene × gene interactions among genes within the same molecular pathway after adjusting for multiple testing via FDR control procedure.
Conclusion
Genetic variation in GHRL may have a modest impact on BMI in European Americans.
doi:10.1159/000181158
PMCID: PMC2715950  PMID: 19077438
Obesity; Body composition; Body mass index; Candidate gene; Ghrelin
19.  The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations 
JIMD Reports  2014;16:75-79.
The inborn errors of metabolism associated with 3-methylglutaconic aciduria are a diverse group of disorders characterized by the excretion of 3-methylglutaconic and 3-methylglutaric acids in the urine. Mutations in several genes have been identified in association with 3-methylglutaconic aciduria. We describe a patient of Saudi Arabian descent with 3-methylglutaconic aciduria, sensorineural hearing loss, encephalopathy, and Leigh-like pattern on MRI (MEGDEL syndrome), as well as developmental delay and developmental regression, bilateral optic nerve atrophy, microcephaly, and myoclonic epilepsy. The patient had an earlier age of onset of optic atrophy than previously described in other MEGDEL syndrome patients. Whole exome sequencing revealed two loss-of-function mutations in SERAC1 in trans: c.438delC (p.T147Rfs*22) and c.442C>T (p.R148X), confirmed by Sanger sequencing. One of these mutations is novel (c.438delC). This case contributes to refining the MEGDEL phenotype.
doi:10.1007/8904_2014_322
PMCID: PMC4221303  PMID: 24997715
20.  Weight Loss after Bariatric Surgery in Morbidly Obese Adolescents with MC4R mutations 
Obesity (Silver Spring, Md.)  2013;22(1):225-231.
Objective
To determine the frequency of Melanocortin4 Receptor (MC4R) mutations in morbidly obese adolescents undergoing bariatric surgery and compare weight loss outcomes in patients with and without mutations.
Design and Methods
In this prospective cohort study, 135 adolescent patients evaluated for bariatric surgery were screened for MC4R mutations; 56 had 12 month postoperative data available for analysis.
Results
MC4R mutations were detected in five of the 135 patients (3.7%); four underwent restrictive bariatric surgery. For the three patients with gastric banding, percent excess weight loss (%EWL) postoperatively was 36.0% at 5 years in one, 47% at 4 years in the second, and 85% at 1 year in the third. For the patient with gastric sleeve resection, %EWL of 96% was attained at 1 year postoperatively. The four MC4R cases had a higher, although non-significant, %EWL compared to 52 non-matched controls at 12 months postoperatively (48.6% vs. 23.4%; p<0.37). When matched by age, sex, and race to 14 controls, there was no significant difference in %EWL (p < 0.31), BMI change (p< 0.27), or absolute weight loss (p <0.20).
Conclusion
The frequency of MC4R mutations is similar to prior studies, with affected patients showing beneficial weight loss outcomes.
doi:10.1002/oby.20511
PMCID: PMC3880391  PMID: 23740648
MC4R; Obesity; Adolescents; Bariatric surgery
21.  Genetic Variants Associated with Breast Cancer Risk for Ashkenazi Jewish Women with Strong Family Histories but No Identifiable BRCA1/2 Mutation 
Human genetics  2013;132(5):523-536.
Background
The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations.
Methods
This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts were comprised of 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation.
Results
A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. Additionally, 6 previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, 3 novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and 3 previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74.
Conclusion
Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations.
doi:10.1007/s00439-013-1269-4
PMCID: PMC4072456  PMID: 23354978
Ashkenazi Jewish; breast cancer; genome-wide association study; SNP; risk model; AUC
22.  Risk of pancreatic cancer in breast cancer families from the Breast Cancer Family Registry 
Background
Increased risk of pancreatic cancer (PC) has been reported in breast cancer (BC) families carrying BRCA1and BRCA2 mutations; however, PC risk in mutation-negative (BRCAX) families has not been explored to date. The aim of this study was to estimate PC risk in high-risk BC families according to the BRCA mutation status.
Methods
A retrospective cohort analysis was applied to estimate standardized incidence ratios (SIR) for PC. A total of 5,799 families with ≥1 BC case tested for mutations in BRCA1 and/or BRCA2 were eligible. Families were divided into four classes: BRCA1, BRCA2, BRCAX with ≥2 BC diagnosed before age 50 (class 3), and the remaining BRCAX families (class 4).
Results
BRCA1 mutation carriers were at increased risk of PC (SIR= 4.11; 95% confidence interval [CI], 2.94-5.76) as were BRCA2 mutation carriers (SIR=5.79; 95% CI, 4.28-7.84). BRCAX family members were also at increased PC risk, which did not appear to vary by number of members with early-onset breast cancer (SIR=1.31; 95%CI, 1.06-1.63 for Class 3 and SIR=1.30; 95%CI, 1.13-1.49 for class 4).
Conclusions
Germline mutations in BRCA1 and BRCA2 are associated with an increased risk of PC. Members of BRCAX families are also at increased risk of PC, pointing to the existence of other genetic factors that increase the risk of both PC and BC.
Impact
This study clarifies the relationship between familial breast cancer and pancreatic cancer. Given its high mortality, PC should be included in risk assessment in familial breast cancer counseling.
doi:10.1158/1055-9965.EPI-12-0195
PMCID: PMC3739843  PMID: 23456555
pancreatic cancer; breast cancer; BRCA1; BRCA2; BRCAX
23.  Processes and factors involved in decisions regarding return of incidental genomic findings in research 
Purpose
Studies have begun exploring whether researchers should return incidental findings in genomic studies, and if so, which findings should be returned; however, how researchers make these decisions— the processes and factors involved—has remained largely unexplored.
Methods
We interviewed 28 genomics researchers in-depth about their experiences and views concerning the return of incidental findings.
Results
Researchers often struggle with questions concerning which incidental findings to return and how to make those decisions. Multiple factors shape their views, including information about the gene variant (e.g., pathogenicity and disease characteristics), concerns about participants’ well-being and researcher responsibility, and input from external entities. Researchers weigh the evidence, yet they face conflicting pressures, with relevant data frequently being unavailable. Researchers vary in who they believe should decide: participants, principal investigators, institutional review boards, and/or professional organizations. Contextual factors can influence these decisions, including policies governing return of results by institutions and biobanks and the study design. Researchers vary in desires for: guidance from institutions and professional organizations, changes to current institutional processes, and community- wide genetics education.
Conclusion
These data, the first to examine the processes by which researchers make decisions regarding the return of genetic incidental findings, highlight several complexities involved and have important implications for future genetics research, policy, and examinations of these issues.
doi:10.1038/gim.2013.140
PMCID: PMC3966970  PMID: 24071801
benefits and risks; decision making; genome sequencing; incidental findings; return of results
24.  Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension 
Nature genetics  2013;45(5):518-521.
Pulmonary arterial hypertension (PAH) is a rare and devastating disease, resulting from progressive obliteration of small caliber pulmonary arteries by proliferating vascular cells, and leading to cardiac failure, with an untreated mean survival of less than three years 1,2. PAH can complicate other pathological conditions, or can occur in the context of genetic mutations causing heritable PAH, or can be considered as idiopathic (iPAH), which represents approximately 40% of all PAH 3,4. Low penetrance dominant BMPR2 mutations are found in ~70% of familial PAH (fPAH), and in ~15% of iPAH which are thereafter considered as heritable PAH 5,6. We conducted a Genome-Wide Association Study (GWAS) based on two independent case-control studies for iPAH and fPAH (without BMPR2 mutations) totaling 625 patients and 1,525 healthy individuals, to identify novel genetic factors associated with iPAH and fPAH (i/fPAH) in the absence of BMPR2 mutations. A genome wide significant association was detected at the CBLN2 locus mapping to 18q22.3, the risk allele being associated with an odds ratio for i/fPAH of 1.97 [1.59 – 2.45] (P = 7.47 x 10−10). CBLN2 is expressed in the lung, particularly in pulmonary vascular endothelial cells, and its expression is increased in explanted lungs from PAH patients and in endothelial cells cultured from explanted PAH lungs.
doi:10.1038/ng.2581
PMCID: PMC3983781  PMID: 23502781
25.  High Prevalence of BRCA1 and BRCA2 Germline Mutations with Loss of Heterozygosity in a Series of Resected Pancreatic Adenocarcinoma and Other Neoplastic Lesions 
Purpose
Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It is unknown if this association is causal.
Experimental Design
This is a single-site study of patients who underwent surgical pancreatic tumor resection and self-identified as Ashkenazi Jewish. DNA from normal pancreatic tissue was genotyped for the three Ashkenazi Jewish BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, and loss of heterozygosity (LOH) was determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was conducted.
Results
Thirty-seven patients underwent surgery for PDAC, seven for intraductal papillary mucinous neoplasm (IPMN), and 19 for other diseases. A high prevalence of BRCA1/2 mutations was found in the surgical cohort (12/63; 19.0%; P < 0.001), PDAC cohort (8/37; 21.6%; P < 0.001), and IPMN cohort (2/7; 28.6%; P =.01) compared with published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%; P < 0.001) and BRCA2 6174delT (10.8%; P < 0.001) in Ashkenazi Jewish patients with PDAC was shown. BRCA1/2 LOH was found in 2 of 4 BRCA1-associated PDACs and 3 of 4 BRCA2-associated PDACs. Positive p53 IHC was found in 5 of 8 BRCA1/2 PDACs.
Conclusions
We show a high prevalence of BRCA1/2 mutations with LOH in an Ashkenazi Jewish cohort of surgically resected PDAC and neoplastic lesions, suggesting that these germline mutations are causal in selected individuals.
doi:10.1158/1078-0432.CCR-12-3020
PMCID: PMC3959126  PMID: 23658460

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