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1. Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders

Author

Abarca-Barriga, Hugo, Al-Haddad, Christiane, Berman, Jeffrey L., Bothun, Erick D., Capasso, Jenina, Chacon-Camacho, Oscar Francisco, Chang, Lan, Christiansen, Stephen P., Ciccarelli, Maria Laura, Cordonnier, Monique, Cox, Gerald F., Curry, Cynthia J., Dagi, Linda R., Lee Dahm, Thomas, David, Karen L., Davitt, Bradley V., De Berardinis, Teresa, Demer, Joseph L., Désir, Julie, D’Esposito, Fabiana, Drack, Arlene V., Eggenberger, Eric, Elder, James E., Elliott, Alexandra T., Epley, K. David, Feldman, Hagit Baris, Ferreira, Carlos R., Flaherty, Maree P., Fulton, Anne B., Gerth-Kahlert, Christina, Gottlob, Irene, Grill, Stephen, Halliday, Dorothy J., Hanisch, Frank, Hay, Eleanor, Heidary, Gena, Holder, Christopher, Horton, Jonathan C., Iannaccone, Alessandro, Isenberg, Sherwin J., Johnston, Suzanne C., Kahana, Alon, Katowitz, James A., Kazlas, Melanie, Kerr, Natalie C., Kimonis, Virginia, Ko, Melissa W., Koc, Feray, Larsen, Dorte Ancher, Lay-Son, Guillermo, Ledoux, Danielle M., Levin, Alex V., Levy, Richard L., Lyons, Christopher J., Mackey, David A., Magli, Adriano, Mantagos, Iason S., Marti, Candice, Maystadt, Isabelle, McKenzie, Fiona, Menezes, Manoj P., Mikail, Claudia N., Miller, David T., Miller, Kathryn Bisceglia, Mills, Monte D., Miyana, Kaori, Moller, H.U., Mullineaux, Lisa, Nishimura, Julie K., Noble, A. Gwendolyn, Pandey, Pramod Kumar, Pavone, Piero, Penzien, Johann, Petersen, Robert, Phalen, James A., Poduri, Annapurna, Polo, Claudia R., Prasov, Lev, Ramos, Feliciano J., Ramos-Caceres, Maria, Robb, Richard M., Rossillion, Béatrice, Sahin, Mustafa, Singer, Harvey S., Smith, Lois E.H., Sorkin, Jeffrey A., Soul, Janet S., Staffieri, Sandra E., Stalker, Heather J., Stasheff, Steven F., Strassberg, Sonya, Strominger, Mitchell B., Taranath, Deepa Ajay, Thomas, Ioan Talfryn, Traboulsi, Elias I., Ugrin, Maria Cristina, VanderVeen, Deborah K., Vincent, Andrea L., Vogel G, Marlene C., Wabbels, Bettina, Wong, Agnes M.F., Woods, C. Geoffrey, Wu, Carolyn, Yang, Edward, Yeung, Alison, Young, Terri L., Zenteno, Juan C., Zubcov-Iwantscheff, Alexandra A., Zwaan, Johan, Jurgens, Julie A., Barry, Brenda J., Chan, Wai-Man, MacKinnon, Sarah, Whitman, Mary C., Matos Ruiz, Paola M., Pratt, Brandon M., England, Eleina M., Pais, Lynn, Lemire, Gabrielle, Groopman, Emily, Glaze, Carmen, Russell, Kathryn A., Singer-Berk, Moriel, Di Gioia, Silvio Alessandro, Lee, Arthur S., Andrews, Caroline, Shaaban, Sherin, Wirth, Megan M., Bekele, Sarah, Toffoloni, Melissa, Bradford, Victoria R., Foster, Emma E., Berube, Lindsay, Rivera-Quiles, Cristina, Mensching, Fiona M., Sanchis-Juan, Alba, Fu, Jack M., Wong, Isaac, Zhao, Xuefang, Wilson, Michael W., Weisburd, Ben, Lek, Monkol, Brand, Harrison, Talkowski, Michael E., MacArthur, Daniel G., O’Donnell-Luria, Anne, Robson, Caroline D., Hunter, David G., and Engle, Elizabeth C.

Published
2024
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3. A critique of behavioural vision therapy techniques for children with reading difficulties including dyslexia.

Author

Flaherty, Maree, Crippa, Jessica, Sim, Irina, Bhate, Manjushree, Chow, Chian Chiang Nicholas, Taranath, Deepa, and Gole, Glen

Abstract

Specific learning disabilities affect the brain's ability to process verbal and non-verbal information efficiently and accurately. The most common learning disability is reading disability which includes dyslexia. Evidence supports that dyslexia is a language-based disorder. The core deficit of dyslexia is the phonological component of language that interferes with reading development. Therefore early, intense and specific remedial therapy should address the underlying cause of the difficulty. Behavioural optometry is controversial and purports to make children more responsive to education by improving visual conditions conducive for learning with eye exercises, tinted/coloured lenses and movment-based exercises. However, the theoretical basis for behavioural therapies have not been well established. Literature which favours behavioural approaches suffers from serious methodological and interpretive flaws. There is currently insufficient evidence to support behavioural approaches which therefore should not be recommended. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Revealing hidden genetic diagnoses in the ocular anterior segment disorders

Author

Ma, Alan, Yousoof, Saira, Grigg, John R., Flaherty, Maree, Minoche, Andre E., Cowley, Mark J., Nash, Benjamin M., Ho, Gladys, Gayagay, Thet, Lai, Tiffany, Farnsworth, Elizabeth, Hackett, Emma L., Fisk, Katrina, Wong, Karen, Holman, Katherine J., Jenkins, Gemma, Cheng, Anson, Martin, Frank, Karaconji, Tanya, Elder, James E., Enriquez, Annabelle, Wilson, Meredith, Amor, David J., Stutterd, Chloe A., Kamien, Benjamin, Nelson, John, Dinger, Marcel E., Bennetts, Bruce, and Jamieson, Robyn V.

Published
2020
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6. Timing of surgery in essential infantile esotropia - What more do we know since the turn of the century?

Author

Bhate, Manjushree, Flaherty, Maree, and Martin, Frank

Subjects
Stereo vision -- Risk factors, Convergent strabismus -- Risk factors -- Diagnosis -- Development and progression, Eye -- Surgery, Health
Abstract

Byline: Manjushree. Bhate, Maree. Flaherty, Frank. Martin This review summarizes the results and interpretations of studies pertaining to the long-standing debate regarding the timing of surgery in infantile esotropia, more [...]

Published
2022

7. Paediatric Horner Syndrome: How much further to investigate?

Author

Bhate, Manjushree, Flaherty, Maree, Rowe, Neil, and Howman-Giles, Robert

Subjects
Horner's syndrome -- Case studies -- Diagnosis -- Care and treatment, Pediatric diseases -- Case studies -- Diagnosis -- Care and treatment, Health
Abstract

Byline: Manjushree. Bhate, Maree. Flaherty, Neil. Rowe, Robert. Howman-Giles We report an infant with an early-onset Horner syndrome and normal urinary catecholamine levels. Further investigations with Nuclear medicine imaging with123I-MIBG [...]

Published
2020

13. Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance

Author

Tischfield, Max A., Baris, Hagit N., Wu, Chen, Rudolph, Guenther, Van Maldergem, Lionel, He, Wei, Chan, Wai-Man, Andrews, Caroline, Demer, Joseph L., Robertson, Richard L., Mackey, David A., Ruddle, Jonathan B., Bird, Thomas D., Gottlob, Irene, Pieh, Christina, Traboulsi, Elias I., Pomeroy, Scott L., Hunter, David G., Soul, Janet S., Newlin, Anna, Sabol, Louise J., Doherty, Edward J., de Uzcátegui, Clara E., de Uzcátegui, Nicolas, Collins, Mary Louise Z., Sener, Emin C., Wabbels, Bettina, Hellebrand, Heide, Meitinger, Thomas, de Berardinis, Teresa, Magli, Adriano, Schiavi, Costantino, Pastore-Trossello, Marco, Koc, Feray, Wong, Agnes M., Levin, Alex V., Geraghty, Michael T., Descartes, Maria, Flaherty, Maree, Jamieson, Robyn V., Møller, H.U., Meuthen, Ingo, Callen, David F., Kerwin, Janet, Lindsay, Susan, Meindl, Alfons, Gupta, Mohan L., Jr., Pellman, David, and Engle, Elizabeth C.

Published
2010
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17. Genome sequencing in congenital cataracts improves diagnostic yield

Author

Ma, Alan, primary, Grigg, John R., additional, Flaherty, Maree, additional, Smith, James, additional, Minoche, Andre E., additional, Cowley, Mark J., additional, Nash, Benjamin M., additional, Ho, Gladys, additional, Gayagay, Thet, additional, Lai, Tiffany, additional, Farnsworth, Elizabeth, additional, Hackett, Emma L., additional, Slater, Katrina, additional, Wong, Karen, additional, Holman, Katherine J., additional, Jenkins, Gemma, additional, Cheng, Anson, additional, Martin, Frank, additional, Brown, Natasha J., additional, Leighton, Sarah E., additional, Amor, David J., additional, Goel, Himanshu, additional, Dinger, Marcel E., additional, Bennetts, Bruce, additional, and Jamieson, Robyn V., additional

Published
2021
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20. NFB-09. ENROLLMENT AND CLINICAL CHARACTERISTICS OF NEWLY DIAGNOSED, NEUROFIBROMATOSIS TYPE 1 ASSOCIATED OPTIC PATHWAY GLIOMA (NF1-OPG): PRELIMINARY RESULTS FROM AN INTERNATIONAL MULTI-CENTER NATURAL HISTORY STUDY

Author

Fisher, Michael J, primary, Liu, Grant T, additional, Ferner, Rosalie E, additional, Gutmann, David H, additional, Listernick, Robert, additional, de Blank, Peter, additional, Zeid, Janice, additional, Ullrich, Nicole J, additional, Heidary, Gena, additional, Bornhorst, Miriam, additional, Stasheff, Steven F, additional, Rosser, Tena, additional, Borchert, Mark, additional, Ardern-Holmes, Simone, additional, Flaherty, Maree, additional, Hummel, Trent R, additional, Motley, W Walker, additional, Bielamowicz, Kevin, additional, Phillips, Paul H, additional, Bouffet, Eric, additional, Reginald, Arun, additional, Wolf, David S, additional, Peragallo, Jason, additional, Van Mater, David, additional, El-Dairi, Mays, additional, Sato, Aimee, additional, Tarczy-Hornoch, Kristina, additional, Klesse, Laura, additional, Hogan, Nick, additional, Foreman, Nick, additional, McCourt, Emily, additional, Allen, Jeffrey, additional, Ranka, Milan, additional, Campen, Cynthia, additional, Beres, Shannon, additional, Moertel, Christopher, additional, Areaux, Ray, additional, Stearns, Duncan, additional, Orge, Faruk, additional, Crawford, John, additional, O’Halloran, Henry, additional, Brodsky, Michael, additional, Esbenshade, Adam J, additional, Donahue, Sean, additional, Cutter, Gary, additional, and Avery, Robert A, additional

Published
2020
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27. Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders

Author

Jurgens, Julie A., Barry, Brenda J., Chan, Wai-Man, MacKinnon, Sarah, Whitman, Mary C., Matos Ruiz, Paola M., Pratt, Brandon M., England, Eleina M., Pais, Lynn, Lemire, Gabrielle, Groopman, Emily, Glaze, Carmen, Russell, Kathryn A., Singer-Berk, Moriel, Di Gioia, Silvio Alessandro, Lee, Arthur S., Andrews, Caroline, Shaaban, Sherin, Wirth, Megan M., Bekele, Sarah, Toffoloni, Melissa, Bradford, Victoria R., Foster, Emma E., Berube, Lindsay, Rivera-Quiles, Cristina, Mensching, Fiona M., Sanchis-Juan, Alba, Fu, Jack M., Wong, Isaac, Zhao, Xuefang, Wilson, Michael W., Weisburd, Ben, Lek, Monkol, Abarca-Barriga, Hugo, Al-Haddad, Christiane, Berman, Jeffrey L., Bothun, Erick D., Capasso, Jenina, Chacon-Camacho, Oscar Francisco, Chang, Lan, Christiansen, Stephen P., Ciccarelli, Maria Laura, Cordonnier, Monique, Cox, Gerald F., Curry, Cynthia J., Dagi, Linda R., Lee Dahm, Thomas, David, Karen L., Davitt, Bradley V., De Berardinis, Teresa, Demer, Joseph L., Désir, Julie, D’Esposito, Fabiana, Drack, Arlene V., Eggenberger, Eric, Elder, James E., Elliott, Alexandra T., Epley, K. David, Feldman, Hagit Baris, Ferreira, Carlos R., Flaherty, Maree P., Fulton, Anne B., Gerth-Kahlert, Christina, Gottlob, Irene, Grill, Stephen, Halliday, Dorothy J., Hanisch, Frank, Hay, Eleanor, Heidary, Gena, Holder, Christopher, Horton, Jonathan C., Iannaccone, Alessandro, Isenberg, Sherwin J., Johnston, Suzanne C., Kahana, Alon, Katowitz, James A., Kazlas, Melanie, Kerr, Natalie C., Kimonis, Virginia, Ko, Melissa W., Koc, Feray, Larsen, Dorte Ancher, Lay-Son, Guillermo, Ledoux, Danielle M., Levin, Alex V., Levy, Richard L., Lyons, Christopher J., Mackey, David A., Magli, Adriano, Mantagos, Iason S., Marti, Candice, Maystadt, Isabelle, McKenzie, Fiona, Menezes, Manoj P., Mikail, Claudia N., Miller, David T., Miller, Kathryn Bisceglia, Mills, Monte D., Miyana, Kaori, Moller, H.U., Mullineaux, Lisa, Nishimura, Julie K., Noble, A. Gwendolyn, Pandey, Pramod Kumar, Pavone, Piero, Penzien, Johann, Petersen, Robert, Phalen, James A., Poduri, Annapurna, Polo, Claudia R., Prasov, Lev, Ramos, Feliciano J., Ramos-Caceres, Maria, Robb, Richard M., Rossillion, Béatrice, Sahin, Mustafa, Singer, Harvey S., Smith, Lois E.H., Sorkin, Jeffrey A., Soul, Janet S., Staffieri, Sandra E., Stalker, Heather J., Stasheff, Steven F., Strassberg, Sonya, Strominger, Mitchell B., Taranath, Deepa Ajay, Thomas, Ioan Talfryn, Traboulsi, Elias I., Ugrin, Maria Cristina, VanderVeen, Deborah K., Vincent, Andrea L., Vogel G, Marlene C., Wabbels, Bettina, Wong, Agnes M.F., Woods, C. Geoffrey, Wu, Carolyn, Yang, Edward, Yeung, Alison, Young, Terri L., Zenteno, Juan C., Zubcov-Iwantscheff, Alexandra A., Zwaan, Johan, Brand, Harrison, Talkowski, Michael E., MacArthur, Daniel G., O’Donnell-Luria, Anne, Robson, Caroline D., Hunter, David G., and Engle, Elizabeth C.

Abstract

To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs).

Published
2024
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29. Advantage of whole exome sequencing over allele-specific and targeted segment sequencing in detection of novel TULP1 mutation in leber congenital amaurosis

Author

Guo, Yiran, Prokudin, Ivan, Yu, Cong, Liang, Jinlong, Xie, Yi, Flaherty, Maree, Tian, Lifeng, Crofts, Stephanie, Wang, Fengxiang, Snyder, James, Donaldson, Craig, Abdel-Magid, Nada, Vazquez, Lyam, Keating, Brendan, Hakonarson, Hakon, Wang, Jun, Jamieson, Robyn V., Guo, Yiran, Prokudin, Ivan, Yu, Cong, Liang, Jinlong, Xie, Yi, Flaherty, Maree, Tian, Lifeng, Crofts, Stephanie, Wang, Fengxiang, Snyder, James, Donaldson, Craig, Abdel-Magid, Nada, Vazquez, Lyam, Keating, Brendan, Hakonarson, Hakon, Wang, Jun, and Jamieson, Robyn V.

Abstract

Background: Leber congenital amaurosis (LCA) is a severe form of retinal dystrophy with marked underlying genetic heterogeneity. Until recently, allele-specific assays and Sanger sequencing of targeted segments were the only available approaches for attempted genetic diagnosis in this condition. A broader next-generation sequencing (NGS) strategy, such as whole exome sequencing, provides an improved molecular genetic diagnostic capacity for patients with these conditions.Materials and Methods: In a child with LCA, an allele-specific assay analyzing 135 known LCA-causing variations, followed by targeted segment sequencing of 61 regions in 14 causative genes was performed. Subsequently, exome sequencing was undertaken in the proband, unaffected consanguineous parents and two unaffected siblings. Bioinformatic analysis used two independent pipelines, BWA-GATK and SOAP, followed by Annovar and SnpEff to annotate the variants.Results: No disease-causing variants were found using the allele-specific or targeted segment Sanger sequencing assays. Analysis of variants in the exome sequence data revealed a novel homozygous nonsense mutation (c.1081C > T, p.Arg361) in TULP1, a gene with roles in photoreceptor function where mutations were previously shown to cause LCA and retinitis pigmentosa. The identified homozygous variant was the top candidate using both bioinformatic pipelines.Conclusions: This study highlights the value of the broad sequencing strategy of exome sequencing for disease gene identification in LCA, over other existing methods. NGS is particularly beneficial in LCA where there are a large number of causative disease genes, few distinguishing clinical features for precise candidate disease gene selection, and few mutation hotspots in any of the known disease genes.

Published
2015

30. Ocular and electrophysiological findings in a patient with Sly syndrome.

Author

Flaherty, Maree, Geering, Katie, Crofts, Stephanie, and Grigg, John

Subjects
*ELECTROPHYSIOLOGY, *SLY syndrome, *GENETIC mutation, *BETA-glucuronidase genes, *ELECTRORETINOGRAPHY, OCULAR radiography
Abstract

Background: Sly syndrome (Mucopolysaccharidosis Type VII) is an autosomal recessive metabolic storage disorder due to mutations in theGUSBgene encoding the enzyme beta-glucuronidase. Deficiency of this lysosomal enzyme impairs the body’s ability to break down the glycosaminoglycans – dermatan, heparan and chondroitin sulphate. Coarse facial features and macrocephaly are typically seen along with bony and skeletal abnormalities, including joint contractures and short stature. Widespread involvement occurs in many other tissues including cardiopulmonary, gastrointestinal, and neurological systems. In view of the rarity of Sly syndrome the ophthalmic features have not been well described.Materials and methods: Case report of a 16-year-old boy with Sly syndrome with serial OCT, ocular ultrasound, and electroretinogram (ERG).Results: Corneal clouding was present but there was no evidence of glaucoma or optic neuropathy. Despite no clinical evidence of retinopathy, electrophysiology showed reduced photopic and scotopic responses, particularly involving the b-wave which appears progressive. OCT showed normal foveal architecture and normal retinal nerve fiber thickness.Conclusion: Corneal clouding was noted in this patient and there is no evidence of glaucoma or optic neuropathy. Although retinopathy has not been previously described in Sly syndrome, the ERG changes in this patient suggest that retinopathy may be a feature of MPS VII. [ABSTRACT FROM PUBLISHER]

Published
2017
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32. Advantage of Whole Exome Sequencing over Allele-Specific and Targeted Segment Sequencing in Detection of NovelTULP1Mutation in Leber Congenital Amaurosis

Author

Guo, Yiran, primary, Prokudin, Ivan, additional, Yu, Cong, additional, Liang, Jinlong, additional, Xie, Yi, additional, Flaherty, Maree, additional, Tian, Lifeng, additional, Crofts, Stephanie, additional, Wang, Fengxiang, additional, Snyder, James, additional, Donaldson, Craig, additional, Abdel-Magid, Nada, additional, Vazquez, Lyam, additional, Keating, Brendan, additional, Hakonarson, Hakon, additional, Wang, Jun, additional, and Jamieson, Robyn V., additional

Published
2014
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34. Novel SOX2 partner-factor domain mutation in a four-generation family

Author

Mihelec, Marija, primary, Abraham, Peter, additional, Gibson, Kate, additional, Krowka, Renata, additional, Susman, Rachel, additional, Storen, Rebecca, additional, Chen, Yongjuan, additional, Donald, Jenny, additional, Tam, Patrick PL, additional, Grigg, John R, additional, Flaherty, Maree, additional, Gole, Glen A, additional, and Jamieson, Robyn V, additional

Published
2009
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36. Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1.

Author

Prokudin, Ivan, Simons, Cas, Grigg, John R, Storen, Rebecca, Kumar, Vikrant, Phua, Zai Y, Smith, James, Flaherty, Maree, Davila, Sonia, and Jamieson, Robyn V

Subjects
GENETICS of eye diseases, HUMAN genetic variation, EXONS (Genetics), HETEROGENEITY, EYE examination
Abstract

Developmental eye diseases, including cataract/microcornea, Peters anomaly and coloboma/microphthalmia/anophthalmia, are caused by mutations encoding many different signalling and structural proteins in the developing eye. All modes of Mendelian inheritance occur and many are sporadic cases, so provision of accurate recurrence risk information for families and affected individuals is highly challenging. Extreme genetic heterogeneity renders testing for all known disease genes clinically unavailable with traditional methods. We used whole-exome sequencing in 11 unrelated developmental eye disease patients, as it provides a strategy for assessment of multiple disease genes simultaneously. We identified five causative variants in four patients in four different disease genes, GJA8, CRYGC, PAX6 and CYP1B1. This detection rate (36%) is high for a group of patients where clinical testing is frequently not undertaken due to lack of availability and cost. The results affected clinical management in all cases. These variants were detected in the cataract/microcornea and Peters anomaly patients. In two patients with coloboma/microphthalmia, variants in ABCB6 and GDF3 were identified with incomplete penetrance, highlighting the complex inheritance pattern associated with this phenotype. In the coloboma/microphthalmia patients, four other variants were identified in CYP1B1, and CYP1B1 emerged as a candidate gene to be considered as a modifier in coloboma/microphthalmia. [ABSTRACT FROM AUTHOR]

Published
2014
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40. EVALUATION OF NINE HUNDRED AND SIXTY-SEVEN CONSECUTIVE INTRAOCULAR IMPLANTS.

Author

KENNEDY, JOHN E., FLAHERTY, MAREE P., HUNYOR, ALEX B. L., and ROBINSON, LYON P.

Abstract

We undertook a survey of all intraocular lenses (lOLs) implanted by two surgeons from 1976 up to the end of 1983. Of the 967 implants, 164 were excluded because of lack of adequate follow-up. Of the remaining 803 cases there were 104 anterior chamber lenses, 185 iris-supported lenses, and 514 posterior chamber lenses. The overall final visual acuity was 6/12 or better in 740 cases (92.2%). Of the remaining 63 cases, 32 had pre-existing disease or associated conditions not directly related to the operation. By analysing the results within each major group of IOL we found that the posterior chamber lOLs had the best final visual acuity (94.4% 6/12 or better) and fewer postoperative complications. The major problems with iris-supported lOLs were corneal decompensation and cystoid macular oedema. [ABSTRACT FROM AUTHOR]

Published
1985
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42. Axenfeld anomaly in association with hypomelanosis of Ito

Author

Flaherty, Maree, Padilla, Carmencita, and Sillence, David

Abstract

Hypomelanosis of Ito is a rare neurocutaneous disorder with associated ocular, facial, dental and skeletal abnormalities. The authors describe a case of hypomelanosis of Ito occurring with anterior segment mesenchymal dysgenesis of the Axenfeld type. An attempt is made to explain many of the major features of hypomelanosis of Ito in terms of neural crest origin, and to classify the disease as a neurocristopathy.

Published
1991
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45. Corneal arcus as the presenting sign of familial hypercholesterolemia in a young child.

Author

Lock JH, Ross CA, and Flaherty M

Subjects
Adult, Arcus Senilis diagnosis, Arcus Senilis genetics, Child, Preschool, Cholesterol, LDL blood, Female, Follow-Up Studies, Genetic Testing, Homozygote, Humans, Hyperlipoproteinemia Type II blood, Hyperlipoproteinemia Type II genetics, Male, Phenotype, Arcus Senilis etiology, Cornea pathology, Hyperlipoproteinemia Type II complications
Abstract

A 2.6-year-old boy presented with prominent corneal arcus. This clinical sign is rarely seen at such a young age and led to the diagnosis of familial hypercholesterolemia (FH). Genetic analysis detected biallelic pathogenic sequence variants c.1069G>A and c.2034C>A in the LDLR gene. There is significant cardiovascular morbidity and mortality associated with FH, hence early diagnosis and treatment is imperative., (Copyright © 2018 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Published
2018
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46. Advantage of Whole Exome Sequencing over Allele-Specific and Targeted Segment Sequencing in Detection of Novel TULP1 Mutation in Leber Congenital Amaurosis.

Author

Guo Y, Prokudin I, Yu C, Liang J, Xie Y, Flaherty M, Tian L, Crofts S, Wang F, Snyder J, Donaldson C, Abdel-Magid N, Vazquez L, Keating B, Hakonarson H, Wang J, and Jamieson RV

Subjects
Amino Acid Sequence, Base Sequence, Child, Consanguinity, DNA Mutational Analysis, Electroretinography, Exome genetics, Female, High-Throughput Nucleotide Sequencing, Humans, Leber Congenital Amaurosis diagnosis, Leber Congenital Amaurosis physiopathology, Molecular Sequence Data, Pedigree, Polymorphism, Single Nucleotide, Visual Acuity physiology, Codon, Nonsense, Eye Proteins genetics, Leber Congenital Amaurosis genetics
Abstract

Background: Leber congenital amaurosis (LCA) is a severe form of retinal dystrophy with marked underlying genetic heterogeneity. Until recently, allele-specific assays and Sanger sequencing of targeted segments were the only available approaches for attempted genetic diagnosis in this condition. A broader next-generation sequencing (NGS) strategy, such as whole exome sequencing, provides an improved molecular genetic diagnostic capacity for patients with these conditions., Materials and Methods: In a child with LCA, an allele-specific assay analyzing 135 known LCA-causing variations, followed by targeted segment sequencing of 61 regions in 14 causative genes was performed. Subsequently, exome sequencing was undertaken in the proband, unaffected consanguineous parents and two unaffected siblings. Bioinformatic analysis used two independent pipelines, BWA-GATK and SOAP, followed by Annovar and SnpEff to annotate the variants., Results: No disease-causing variants were found using the allele-specific or targeted segment Sanger sequencing assays. Analysis of variants in the exome sequence data revealed a novel homozygous nonsense mutation (c.1081C > T, p.Arg361*) in TULP1, a gene with roles in photoreceptor function where mutations were previously shown to cause LCA and retinitis pigmentosa. The identified homozygous variant was the top candidate using both bioinformatic pipelines., Conclusions: This study highlights the value of the broad sequencing strategy of exome sequencing for disease gene identification in LCA, over other existing methods. NGS is particularly beneficial in LCA where there are a large number of causative disease genes, few distinguishing clinical features for precise candidate disease gene selection, and few mutation hotspots in any of the known disease genes.

Published
2015
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