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Dive into the research topics where Christopher Barnett is active.

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Featured researches published by Christopher Barnett.


American Journal of Human Genetics | 2013

Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

Yoko Aoki; Tetsuya Niihori; Toshihiro Banjo; Nobuhiko Okamoto; Seiji Mizuno; Kenji Kurosawa; Tsutomu Ogata; Fumio Takada; Michihiro Yano; Toru Ando; Tadataka Hoshika; Christopher Barnett; Hirofumi Ohashi; Hiroshi Kawame; Tomonobu Hasegawa; Takahiro Okutani; Tatsuo Nagashima; Satoshi Hasegawa; Ryo Funayama; Takeshi Nagashima; Keiko Nakayama; Shin-ichi Inoue; Yusuke Watanabe; Toshihiko Ogura; Yoichi Matsubara

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.


Nature Genetics | 2012

Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.

Pei Wen Chiang; Juan Wang; Yang Chen; Quan Fu; Jing Zhong; Yanhua Chen; Xin Yi; Renhua Wu; Haixue Gan; Yong Shi; Yanling Chen; Christopher Barnett; Dianna Wheaton; Megan A Day; Joanne Sutherland; Elise Héon; Richard G. Weleber; Luis Alexandre Rassi Gabriel; Peikuan Cong; Kuang-Hsiang Chuang; Sheng Ye; Juliana Maria Ferraz Sallum; Ming Qi

Leber congenital amaurosis (LCA) is an autosomal recessive retinal dystrophy that manifests with genetic heterogeneity. We sequenced the exome of an individual with LCA and identified nonsense (c.507G>A, p.Trp169*) and missense (c.769G>A, p.Glu257Lys) mutations in NMNAT1, which encodes an enzyme in the nicotinamide adenine dinucleotide (NAD) biosynthesis pathway implicated in protection against axonal degeneration. We also found NMNAT1 mutations in ten other individuals with LCA, all of whom carry the p.Glu257Lys variant.


Nature Genetics | 2017

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Holly A.F. Stessman; Bo Xiong; Bradley P. Coe; Tianyun Wang; Kendra Hoekzema; Michaela Fenckova; Malin Kvarnung; Jennifer Gerdts; Sandy Trinh; Nele Cosemans; Laura Vives; Janice Lin; Tychele N. Turner; Gijs W.E. Santen; Claudia Ruivenkamp; Marjolein Kriek; Arie van Haeringen; Emmelien Aten; Kathryn Friend; Jan Liebelt; Christopher Barnett; Eric Haan; Marie Shaw; Jozef Gecz; Britt Marie Anderlid; Ann Nordgren; Anna Lindstrand; Charles E. Schwartz; R. Frank Kooy; Geert Vandeweyer

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.


Journal of Pediatric Gastroenterology and Nutrition | 1999

Reproducibility of the 13C-octanoic acid breath test for assessment of gastric emptying in healthy preterm infants

Christopher Barnett; Antonie Snel; Taher Omari; Geoff Davidson; Ross Haslam; Ross N. Butler

BACKGROUND The 13C-octanoic acid breath test has been used to measure gastric emptying in preterm infants, but the reproducibility of the test has not been evaluated in this population. METHODS Fifty-six paired breath test analyses were performed on 28 healthy preterm infants 1 to 5 days apart using the same food type, volume, and energy content for each paired sample. Breath samples were taken before the feeding, at 5-minute intervals after feeding for 30 minutes, then each 15 minutes for 4 hours. Samples were analyzed using an isotope-ratio mass spectrometer, and 3C recovery was used to calculate values for gastric-emptying coefficient and gastric half-emptying time. RESULTS There was no significant difference between test results on different days in the paired samples studied. gastric-emptying coefficients for the first and subsequent samples were 2.6+/-0.1 (mean+/-SEM) and 2.7+/-0.1, respectively, and half-emptying times were 44.5+/-3.7 minutes and 41.4+/-3.2 minutes. CONCLUSION The 13C-octanoic acid breath test is a reliable, noninvasive, and reproducible measure of gastric emptying in preterm infants that should have wide application for use in this population.


Human Mutation | 2015

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

Kitiwan Rojnueangnit; Jing Xie; Alicia Gomes; Angela Sharp; Tom Callens; Yunjia Chen; Ying Liu; Meagan Cochran; Mary Alice Abbott; Joan F. Atkin; Dusica Babovic-Vuksanovic; Christopher Barnett; Melissa Crenshaw; Dennis Bartholomew; Lina Basel; Gary Bellus; Shay Ben-Shachar; Martin G. Bialer; David P. Bick; Bruce Blumberg; Fanny Cortés; Karen L. David; Anne Destrée; Anna Duat-Rodriguez; Dawn Earl; Luis F. Escobar; Marthanda Eswara; Begona Ezquieta; Ian Frayling; Moshe Frydman

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype–phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café‐au‐lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan‐like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1‐patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi‐exon deletion, providing genetic evidence that p.Arg1809Cys is a loss‐of‐function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype–phenotype correlation will affect counseling and management of a significant number of patients.


American Journal of Physiology-gastrointestinal and Liver Physiology | 1999

Measurement of upper esophageal sphincter tone and relaxation during swallowing in premature infants

Taher Omari; A. Snel; Christopher Barnett; Geoffrey P. Davidson; Ross Haslam

Upper esophageal sphincter (UES) motor function has not been previously evaluated in premature infants. The motor patterns associated with tonic activity and swallow-related relaxation of the UES were recorded for 1 h after completion of gavage feeding in 11 healthy preterm neonates (postmenstrual age 33-37 wk) with a micromanometric assembly, which included a sleeve sensor specifically adapted for UES recordings. A clearly defined UES high-pressure zone was observed in all premature infants studied. Resting UES pressure ranged from 2.3 to 26.2 mmHg and was higher during periods of irritability and apparent discomfort. During dry swallows, UES pressure relaxed from a resting pressure of 28.2 ± 4.0 mmHg to a nadir of 1.1 ± 3.3 mmHg. The mean UES relaxation interval (the time from relaxation onset to relaxation offset) was 0.31 ± 0.11 s. We conclude that in premature infants ≥33 wk postmenstrual age the motor mechanisms regulating UES resting pressure and the onset of UES relaxation are well developed.


Lancet Neurology | 2015

Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study

Ghayda M. Mirzaa; Valerio Conti; Andrew E. Timms; Christopher D. Smyser; Sarah Ahmed; Melissa T. Carter; Sarah S. Barnett; Robert B. Hufnagel; Amy Goldstein; Yoko Narumi-Kishimoto; Carissa Olds; Sarah Collins; Kathreen Johnston; Jean-François Deleuze; Patrick Nitschke; Kathryn Friend; Catharine J. Harris; Allison L. Goetsch; Beth Martin; Evan A. Boyle; Elena Parrini; Davide Mei; Lorenzo Tattini; Anne Slavotinek; Ed Blair; Christopher Barnett; Jay Shendure; Jamel Chelly; William B. Dobyns; Renzo Guerrini

SUMMARY Background Bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria, causes the congenital bilateral perisylvian syndrome, featuring oromotor dysfunction, cognitive impairment and epilepsy. BPP is etiologically heterogeneous, but only a few genetic causes have been reported. The aim of this study was to identify additional genetic etiologies of BPP and delineate their frequency in this patient population. Methods We performed child-parent (trio)-based whole exome sequencing (WES) on eight children with BPP. Following the identification of mosaic PIK3R2 mutations in two of these eight children, we performed targeted screening of PIK3R2 in a cohort of 118 children with BPP who were ascertained from 1980 until 2015 using two methods. First, we performed targeted sequencing of the entire PIK3R2 gene by single molecule molecular inversion probes (smMIPs) on 38 patients with BPP with normal-large head size. Second, we performed amplicon sequencing of the recurrent PIK3R2 mutation (p.Gly373Arg) on 80 children with various types of polymicrogyria including BPP. One additional patient underwent clinical WES independently, and was included in this study given the phenotypic similarity to our cohort. All patients included in this study were children (< 18 years of age) with polymicrogyria enrolled in our research program. Findings Using WES, we identified a mosaic mutation (p.Gly373Arg) in the regulatory subunit of the PI3K-AKT-MTOR pathway, PIK3R2, in two children with BPP. Of the 38 patients with BPP and normal-large head size who underwent targeted next generation sequencing by smMIPs, we identified constitutional and mosaic PIK3R2 mutations in 17 additional children. In parallel, one patient was found to have the recurrent PIK3R2 mutation by clinical WES. Seven patients had BPP alone, and 13 had BPP in association with features of the megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH). Nineteen patients had the same mutation (Gly373Arg), and one had a nearby missense mutation (p.Lys376Glu). Across the entire cohort, mutations were constitutional in 12 and mosaic in eight patients. Among mosaic patients, we observed substantial variation in alternate (mutant) allele levels ranging from 2·5% (10/377) to 36·7% (39/106) of reads, equivalent to 5–73·4% of cells analyzed. Levels of mosaicism varied from undetectable to 17·1% (37/216) of reads in blood-derived compared to 29·4% (2030/6889) to 43·3% (275/634) in saliva-derived DNA. Interpretation Constitutional and mosaic mutations in the PIK3R2 gene are associated with a spectrum of developmental brain disorders ranging from BPP with a normal head size to the megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The phenotypic variability and low-level mosaicism challenging conventional molecular methods have important implications for genetic testing and counseling.


European Journal of Human Genetics | 2011

Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment?

Christopher Barnett; David Chitayat; Timothy J. Bradley; Yanting Wang; Aleksander Hinek

Loeys–Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by facial dysmorphism, cleft palate, dilation of the aortic arch, blood vessel tortuosity and a high risk of aortic dissection. It is caused by mutations in the transforming growth factor β-receptor 1 and 2 (TGFβ-R1 and TGFβ-R2) genes. Fibroblasts derived from 12 Loeys–Dietz syndrome patients, six with TGFB-R1 mutations and six with TGFB-R2 mutations, were analyzed using RT-PCR, biochemical assays, immunohistochemistry and electron microscopy for production of elastin, fibrillin 1, fibulin 1 and fibulin 4 and deposition of collagen type I. All LDS fibroblasts with TGFβ-R1 mutations demonstrated decreased expression of elastin and fibulin 1 genes and impaired deposition of elastic fibers. In contrast, fibroblasts with TGFβ-R2 mutations consistently demonstrated intracellular accumulation of collagen type I in the presence of otherwise normal elastic fiber production. Treatment of the cell cultures with dexamethasone induced remarkable upregulation in the expression of tropoelastin, fibulin 1- and fibulin 4-encoding mRNAs, leading to normalization of elastic fiber production in fibroblasts with TGFβ-R1 mutations. Treatment with dexamethasone also corrected the abnormal secretion of collagen type I from fibroblasts with TGFβ-R2 gene mutations. As the organogenesis-relevant elastic fiber production occurs exclusively in late fetal and early neonatal life, these findings may have implications for treatment in early life. Further studies are required to determine if dexamethasone treatment of fetuses prenatally diagnosed with LDS would prevent or alleviate the connective tissue and vascular defects seen in this syndrome.


Nature Neuroscience | 2017

Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Madeleine Geisheker; Gabriel Heymann; Tianyun Wang; Bradley P. Coe; Tychele N. Turner; Holly A.F. Stessman; Kendra Hoekzema; Malin Kvarnung; Marie Shaw; Kathryn Friend; Jan Liebelt; Christopher Barnett; Elizabeth Thompson; Eric Haan; Hui Guo; Britt Marie Anderlid; Ann Nordgren; Anna Lindstrand; Geert Vandeweyer; Antonino Alberti; Emanuela Avola; Mirella Vinci; Stefania Giusto; Tiziano Pramparo; Karen Pierce; Srinivasa Nalabolu; Jacob J. Michaelson; Zdenek Sedlacek; Gijs W.E. Santen; Hilde Peeters

Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.


American Journal of Medical Genetics Part A | 2012

Choreoathetosis, congenital hypothyroidism and neonatal respiratory distress syndrome with intact NKX2‐1

Christopher Barnett; Justin J. Mencel; Jozef Gecz; Wendy Waters; Susan M. Kirwin; Kathy M. B. Vinette; Miriam Uppill; Jillian Nicholl

Mutations in the NK2 homeobox 1 gene (NKX2‐1) cause a rare syndrome known as choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome (OMIM 610978). Here we present the first reported patient with this condition caused by a 14q13.3 deletion which is adjacent to but does not interrupt NKX2‐1, and review the literature on this condition. The infant presented at 23 months with a history of developmental delay, hyperkinesia, recurrent respiratory infections, neonatal respiratory distress, and hypothyroidism. Choreiform movements and delayed motor milestones were first noted at 6–8 months of age. TSH levels had been consistently elevated from 8 months of age. The clinical presentation was suggestive of an NKX2‐1 mutation. Sequencing of all exons and splice site junctions of NKX2‐1 was performed but was normal. Array CGH was then performed and a 3.29 Mb interstitial deletion at 14q13.1–q13.3 was detected. The distal region of loss of the deletion disrupted the surfactant associated 3 (SFTA3) gene but did disrupt NKX2‐1. Findings were confirmed on high resolution SNP array and multiplex semiquanitative PCR. NKX2‐1 encodes transcriptional factors involved in the developmental pathways for thyroid, lung, and brain. We hypothesize that the region centromeric to NKX2‐1 is important for the normal functioning of this gene and when interrupted produces a phenotype that is typical of the choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome, as seen in our patient. We conclude that deletions at 14q13.3 adjacent to but not involving NKX2‐1 can cause choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome.

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Ross Haslam

Boston Children's Hospital

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Taher Omari

University of Adelaide

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John Dent

University of Adelaide

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Geoff Davidson

Boston Children's Hospital

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Jillian Nicholl

Boston Children's Hospital

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Eric Haan

University of Adelaide

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Kathryn Friend

Boston Children's Hospital

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Wendy Waters

Boston Children's Hospital

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