29 results on '"Ewans L"'
Search Results
2. Distinctive Brain Malformations in Zhu-Tokita-Takenouchi-Kim Syndrome
- Author
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Halliday, B.J., primary, Baynam, G., additional, Ewans, L., additional, Greenhalgh, L., additional, Leventer, R.J., additional, Pilz, D.T., additional, Sachdev, R., additional, Scheffer, I.E., additional, Markie, D.M., additional, McGillivray, G., additional, Robertson, S.P., additional, and Mandelstam, S., additional
- Published
- 2022
- Full Text
- View/download PDF
3. A duplication in a patient with 46,XX ovo‐testicular disorder of sex development refines the SOX9 testis‐specific regulatory region to 24 kb
- Author
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Ohnesorg, T., van den Bergen, J.A., Belluoccio, D., Shankara‐Narayana, N., Kean, A.‐M., Vasilaras, A., Ewans, L., Ayers, K.L., and Sinclair, A.H.
- Published
- 2017
- Full Text
- View/download PDF
4. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity
- Author
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Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Gonçalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, JB, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Guillen Sacoto, MJ, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Adès, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, Lyon, GJ, Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Gonçalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, JB, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Guillen Sacoto, MJ, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Adès, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, and Lyon, GJ
- Abstract
We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TATA-box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X.
- Published
- 2020
5. The first 500 diagnostic exomes: A demonstration of safety, clinical utility, translation and cost-effectiveness.
- Author
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Wilson M., Cliffe C., Elakis G., Zhu Y., Nixon C., Smith J., Turner A., Walsh M., Wallis M., Roscioli T., Worgan L., Schofield D., Lau C., Kirk E., Mead S., Buckley M., Hunter M., Fahey M., Mullan G., Lang S., Richards A., Quayum N., Ades L., Amor D., Bakshi M., Berman Y., Brown N., Chung C., Colley A., Collins F., Edwards M., Ellaway C., Ewans L., Field M., Freckmann M., Gabbett M., Goel H., Ghedia S., Goodwin L., Hackett A., Jones K., Josephi-Taylor S., Kamian B., Kennedy D., Ma A., McGillivray G., Mowat D., Palmer E., Pinner J., Rajagopalan S., Ronan A., Sachdev R., Sandaradura S., Sinnerbrink I., Wilson M., Cliffe C., Elakis G., Zhu Y., Nixon C., Smith J., Turner A., Walsh M., Wallis M., Roscioli T., Worgan L., Schofield D., Lau C., Kirk E., Mead S., Buckley M., Hunter M., Fahey M., Mullan G., Lang S., Richards A., Quayum N., Ades L., Amor D., Bakshi M., Berman Y., Brown N., Chung C., Colley A., Collins F., Edwards M., Ellaway C., Ewans L., Field M., Freckmann M., Gabbett M., Goel H., Ghedia S., Goodwin L., Hackett A., Jones K., Josephi-Taylor S., Kamian B., Kennedy D., Ma A., McGillivray G., Mowat D., Palmer E., Pinner J., Rajagopalan S., Ronan A., Sachdev R., Sandaradura S., and Sinnerbrink I.
- Abstract
Purpose: Whole exome sequencing (WES) is rapidly becoming the standard of care for genetic services. We present the results of 500 clinical exomes performed at the Randwick Genetic Laboratory. Method(s): WES was performed in 204 probands with suspected Mendelian disorders, together with family members. Ampliseq RDY exome, libraries were analyzed on a Life Technologies Proton instrument. Data were analyzed using an in house pipeline with variant reporting following ACMG guidelines. Result(s): WES resulted in greater than 43% definitive findings with a small number of variants of uncertain significance. The diagnostic rate has increased over time, likely reflecting refinements in clinician referral practice as well as improved functionality of bioinformatics pipelines. Two families (1%)with Cantu and MoyaMoya syndromes had results which could lead to pharmacologic interventions. 33 families (16%) had De novo variants and seven (3.5%) were X-linked with significant implications for recurrence risk. Two prenatal diagnoses have been performed based on WES results. A diagnosis was made in 6/8 (75%) rapid turnaround studies, including two during pregnancy. Almost 10% of the diagnoses were unanticipated by the clinical teams and involved significant changes in diagnostic category. Four likely novel genes involved in known biological pathways were identified, enabling research participation. Conclusion(s): The minimum number of management changing outcomes was at least 20% within the 12 month period of this study. The number of secondary findings was small at about 1%. This demonstrates that WES is characterized by high levels of patient safety and clinical utility with likely cost effectiveness.
- Published
- 2019
6. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity
- Author
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Cheng, H., Capponi, S., Wakeling, E., Marchi, E., Li, Q., Zhao, M., Weng, C., Stefan, P.G., Ahlfors, H., Kleyner, R., Rope, A., Lumaka, A., Lukusa, P., Devriendt, K., Vermeesch, J., Posey, J.E., Palmer, E.E., Murray, L., Leon, E., Diaz, J., Worgan, L., Mallawaarachchi, A., Vogt, J., Munnik, S.A., Dreyer, L., Baynam, G., Ewans, L., Stark, Z., Lunke, S., Gonçalves, A.R., Soares, G., Oliveira, J., Fassi, E., Willing, M., Waugh, J.L., Faivre, L., Riviere, J‐B, Moutton, S., Mohammed, S., Payne, K., Walsh, L., Begtrup, A., Guillen Sacoto, M.J., Douglas, G., Alexander, N., Buckley, M.F., Mark, P.R., Adès, L.C., Sandaradura, S.A., Lupski, J.R., Roscioli, T., Agrawal, P.B., Kline, A.D., Wang, K., Timmers, H.T.M., Lyon, G.J., Cheng, H., Capponi, S., Wakeling, E., Marchi, E., Li, Q., Zhao, M., Weng, C., Stefan, P.G., Ahlfors, H., Kleyner, R., Rope, A., Lumaka, A., Lukusa, P., Devriendt, K., Vermeesch, J., Posey, J.E., Palmer, E.E., Murray, L., Leon, E., Diaz, J., Worgan, L., Mallawaarachchi, A., Vogt, J., Munnik, S.A., Dreyer, L., Baynam, G., Ewans, L., Stark, Z., Lunke, S., Gonçalves, A.R., Soares, G., Oliveira, J., Fassi, E., Willing, M., Waugh, J.L., Faivre, L., Riviere, J‐B, Moutton, S., Mohammed, S., Payne, K., Walsh, L., Begtrup, A., Guillen Sacoto, M.J., Douglas, G., Alexander, N., Buckley, M.F., Mark, P.R., Adès, L.C., Sandaradura, S.A., Lupski, J.R., Roscioli, T., Agrawal, P.B., Kline, A.D., Wang, K., Timmers, H.T.M., and Lyon, G.J.
- Abstract
We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X‐linked gene TATA‐box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype‐first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X.
- Published
- 2019
7. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity
- Author
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Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Goncalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, J-B, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Sacoto, MJG, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Ades, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, Lyon, GJ, Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Goncalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, J-B, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Sacoto, MJG, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Ades, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, and Lyon, GJ
- Abstract
We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.
- Published
- 2019
8. Development of a WT1 protein vaccine: 361
- Author
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Gaiger, A., Mossman, S., Reese, V., Smithgall, M., McNeill, P., Ewans, L., Ordonez, N., and Cheever, M. A.
- Published
- 2002
9. Silver Russel syndrome in an Aboriginal patient from Australia
- Author
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Poulton, C., Azmanov, D., Atkinson, V., Beilby, J., Ewans, L., Gration, D., Dreyer, L., Shetty, V., Peake, C., McCormack, E., Palmer, Richard, Lewis, B., Dawkins, H., Broley, S., Baynam, G., Poulton, C., Azmanov, D., Atkinson, V., Beilby, J., Ewans, L., Gration, D., Dreyer, L., Shetty, V., Peake, C., McCormack, E., Palmer, Richard, Lewis, B., Dawkins, H., Broley, S., and Baynam, G.
- Abstract
Silver-Russell syndrome (SRS OMIM 180860) is a rare, albeit well-recognized disorder characterized by severe intrauterine and postnatal growth retardation. It remains a clinical diagnosis with a molecular cause identifiable in approximately 60%–70% of patients. We report a 4-year-old Australian Aboriginal girl who was born at 32 weeks gestation with features strongly suggestive of SRS, after extensive investigation she was referred to our undiagnosed disease program (UDP). Genomic sequencing was performed which identified a heterozygous splice site variant in IGF2 which is predicted to be pathogenic by in-silico studies, paternal allelic origin, de novo status, and RNA studies on fibroblasts. We compare clinical findings with reported patients to add to the knowledge base on IGF2 variants and to promote the engagement of other Australian Aboriginal families in genomic medicine.
- Published
- 2018
10. A duplication in a patient with 46,XX ovo-testicular disorder of sex development refines the SOX9 testis-specific regulatory region to 24 kb
- Author
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Ohnesorg, T, van den Bergen, JA, Belluoccio, D, Shankara-Narayana, N, Kean, A-M, Vasilaras, A, Ewans, L, Ayers, KL, Sinclair, AH, Ohnesorg, T, van den Bergen, JA, Belluoccio, D, Shankara-Narayana, N, Kean, A-M, Vasilaras, A, Ewans, L, Ayers, KL, and Sinclair, AH
- Abstract
A custom CGH microarray that covers the SOX9 regulatory region. Log2 ratio scatterplot showing individual data points. Blue box highlights copy number gain with 3' breakpoint region magnified.
- Published
- 2017
11. Painful ovulation in a 46, XX SRY - ve adult male with SOX9 duplication
- Author
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Narayana, NS, Kean, A-M, Ewans, L, Ohnesorg, T, Ayers, KL, Watson, G, Vasilaras, A, Sinclair, AH, Twigg, SM, Handelsman, DJ, Narayana, NS, Kean, A-M, Ewans, L, Ohnesorg, T, Ayers, KL, Watson, G, Vasilaras, A, Sinclair, AH, Twigg, SM, and Handelsman, DJ
- Abstract
UNLABELLED: 46,XX disorders of sexual development (DSDs) occur rarely and result from disruptions of the genetic pathways underlying gonadal development and differentiation. We present a case of a young phenotypic male with 46,XX SRY-negative ovotesticular DSD resulting from a duplication upstream of SOX9 presenting with a painful testicular mass resulting from ovulation into an ovotestis. We present a literature review of ovulation in phenotypic men and discuss the role of SRY and SOX9 in testicular development, including the role of SOX9 upstream enhancer region duplication in female-to-male sex reversal. LEARNING POINTS: In mammals, the early gonad is bipotent and can differentiate into either a testis or an ovary. SRY is the master switch in testis determination, responsible for differentiation of the bipotent gonad into testis.SRY activates SOX9 gene, SOX9 as a transcription factor is the second major gene involved in male sex determination. SOX9 drives the proliferation of Sertoli cells and activates AMH/MIS repressing the ovary. SOX9 is sufficient to induce testis formation and can substitute for SRY function.Assessing karyotype and then determination of the presence or absence of Mullerian structures are necessary serial investigations in any case of DSD, except for mixed gonadal dysgenesis identified by karyotype alone.Treatment is ideal in a multidisciplinary setting with considerations to genetic (implications to family and reproductive recurrence risk), psychological aspects (sensitive individualized counseling including patient gender identity and preference), endocrinological (hormone replacement), surgical (cosmetic, prophylactic gonadectomy) fertility preservation and reproductive opportunities and metabolic health (cardiovascular and bones).
- Published
- 2017
12. Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort.
- Author
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Srinivasan S., Khadilkar A., Bhatia V., Dung V.C., Atta I., Raza J., thi Diem Chi N., Eggers S., Sadedin S., van den Bergen J.A., Robevska G., Ohnesorg T., Hewitt J., Lambeth L., Bouty A., Knarston I.M., Tan T.Y., Cameron F., Werther G., Hutson J., O'Connell M., Grover S.R., Heloury Y., Zacharin M., Bergman P., Kimber C., Brown J., Webb N., Hunter M.F., Titmuss A., Verge C.F., Mowat D., Smith G., Smith J., Ewans L., Shalhoub C., Crock P., Cowell C., Leong G.M., Ono M., Lafferty A.R., Huynh T., Visser U., Choong C.S., McKenzie F., Pachter N., Thompson E.M., Couper J., Baxendale A., Gecz J., Wheeler B.J., Jefferies C., MacKenzie K., Hofman P., Carter P., King R.I., Krausz C., van Ravenswaaij-Arts C.M.A., Looijenga L., Drop S., Riedl S., Cools M., Dawson A., Juniarto A.Z., Khadilkar V., Hao T.K., Harley V., Koopman P., Warne G., Faradz S., Oshlack A., Ayers K.L., Sinclair A.H., Srinivasan S., Khadilkar A., Bhatia V., Dung V.C., Atta I., Raza J., thi Diem Chi N., Eggers S., Sadedin S., van den Bergen J.A., Robevska G., Ohnesorg T., Hewitt J., Lambeth L., Bouty A., Knarston I.M., Tan T.Y., Cameron F., Werther G., Hutson J., O'Connell M., Grover S.R., Heloury Y., Zacharin M., Bergman P., Kimber C., Brown J., Webb N., Hunter M.F., Titmuss A., Verge C.F., Mowat D., Smith G., Smith J., Ewans L., Shalhoub C., Crock P., Cowell C., Leong G.M., Ono M., Lafferty A.R., Huynh T., Visser U., Choong C.S., McKenzie F., Pachter N., Thompson E.M., Couper J., Baxendale A., Gecz J., Wheeler B.J., Jefferies C., MacKenzie K., Hofman P., Carter P., King R.I., Krausz C., van Ravenswaaij-Arts C.M.A., Looijenga L., Drop S., Riedl S., Cools M., Dawson A., Juniarto A.Z., Khadilkar V., Hao T.K., Harley V., Koopman P., Warne G., Faradz S., Oshlack A., Ayers K.L., and Sinclair A.H.
- Abstract
Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Result(s): We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusion(s): Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.Copyright © 2016 The Author(s).
- Published
- 2016
13. Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort
- Author
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Eggers, S. (Stefanie), Sadedin, S. (Simon), van den Bergen, J.A. (Jocelyn A.), Robevska, G. (Gorjana), Ohnesorg, T. (Thomas), Hewitt, J. (Joanne), Lambeth, L. (Luke), Bouty, A. (Aurore), Knarston, I.M. (Ingrid M.), Tan, T.Y. (Tiong Yang), Cameron, F.J. (Fergus), Werther, G. (George), Hutson, J. (John), O'Connell, M. (Michele), Grover, S.R. (Sonia R.), Heloury, Y. (Yves), Zacharin, M. (Margaret), Bergman, P. (Philip), Kimber, C. (Chris), Brown, J. (Justin), Webb, N. (Nathalie), Hunter, M.F. (Matthew F.), Shubha Srinivasan, Titmuss, A. (Angela), Verge, C.F. (Charles F.), Mowat, D. (David), Smith, G. (Grahame), Smith, J. (Janine), Ewans, L. (Lisa), Shalhoub, C. (Carolyn), Crock, P. (Patricia), Cowell, C. (Chris), Leong, G.M. (GaryM.), Ono, M. (Makato), Lafferty, A.R. (Antony R.), Huynh, T. (Tony), Visser, U. (Uma), Choong, C.S. (Catherine S.), McKenzie, F. (Fiona), Pachter, N. (Nicholas), Thompson, E.M. (Elizabeth M.), Couper, J. (Jennifer), Baxendale, A. (Anne), Gecz, J. (Jozef), Wheeler, B.J. (Benjamin J.), Jefferies, C. (Craig), MacKenzie, K. (Karen), Hofman, P. (Paul), Carter, P. (Philippa), King, R.I. (Richard I.), Krausz, C. (Csilla), Ravenswaaij-Arts, C.M.A. (Conny) van, Looijenga, L.H.J. (Leendert), Drop, S. (Sten), Riedl, S. (Stefan), Cools, M.B.C.M. (Martine), Dawson, A. (Angelika), Juniarto, A.Z. (Achmad), Khadilkar, V. (Vaman), Khadilkar, A. (Anuradha), Bhatia, V. (Vijayalakshmi), Dũng, V.C. (Vũ Chí), Atta, I. (Irum), Raza, J. (Jamal), thi Diem Chi, N. (Nguyen), Hao, T.K. (Tran Kiem), Harley, V.R. (Vincent), Koopman, P. (Peter), Warne, G. (Garry), Faradz, S.M.H. (Sultana), Oshlack, A. (Alicia), Ayers, K.L. (Katie L.), Sinclair, A. (Andrew), Eggers, S. (Stefanie), Sadedin, S. (Simon), van den Bergen, J.A. (Jocelyn A.), Robevska, G. (Gorjana), Ohnesorg, T. (Thomas), Hewitt, J. (Joanne), Lambeth, L. (Luke), Bouty, A. (Aurore), Knarston, I.M. (Ingrid M.), Tan, T.Y. (Tiong Yang), Cameron, F.J. (Fergus), Werther, G. (George), Hutson, J. (John), O'Connell, M. (Michele), Grover, S.R. (Sonia R.), Heloury, Y. (Yves), Zacharin, M. (Margaret), Bergman, P. (Philip), Kimber, C. (Chris), Brown, J. (Justin), Webb, N. (Nathalie), Hunter, M.F. (Matthew F.), Shubha Srinivasan, Titmuss, A. (Angela), Verge, C.F. (Charles F.), Mowat, D. (David), Smith, G. (Grahame), Smith, J. (Janine), Ewans, L. (Lisa), Shalhoub, C. (Carolyn), Crock, P. (Patricia), Cowell, C. (Chris), Leong, G.M. (GaryM.), Ono, M. (Makato), Lafferty, A.R. (Antony R.), Huynh, T. (Tony), Visser, U. (Uma), Choong, C.S. (Catherine S.), McKenzie, F. (Fiona), Pachter, N. (Nicholas), Thompson, E.M. (Elizabeth M.), Couper, J. (Jennifer), Baxendale, A. (Anne), Gecz, J. (Jozef), Wheeler, B.J. (Benjamin J.), Jefferies, C. (Craig), MacKenzie, K. (Karen), Hofman, P. (Paul), Carter, P. (Philippa), King, R.I. (Richard I.), Krausz, C. (Csilla), Ravenswaaij-Arts, C.M.A. (Conny) van, Looijenga, L.H.J. (Leendert), Drop, S. (Sten), Riedl, S. (Stefan), Cools, M.B.C.M. (Martine), Dawson, A. (Angelika), Juniarto, A.Z. (Achmad), Khadilkar, V. (Vaman), Khadilkar, A. (Anuradha), Bhatia, V. (Vijayalakshmi), Dũng, V.C. (Vũ Chí), Atta, I. (Irum), Raza, J. (Jamal), thi Diem Chi, N. (Nguyen), Hao, T.K. (Tran Kiem), Harley, V.R. (Vincent), Koopman, P. (Peter), Warne, G. (Garry), Faradz, S.M.H. (Sultana), Oshlack, A. (Alicia), Ayers, K.L. (Katie L.), and Sinclair, A. (Andrew)
- Abstract
Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively p
- Published
- 2016
- Full Text
- View/download PDF
14. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
- Author
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Eggers, S, Sadedin, S, van den Bergen, JA, Robevska, G, Ohnesorg, T, Hewitt, J, Lambeth, L, Bouty, A, Knarston, IM, Tiong, YT, Cameron, F, Werther, G, Hutson, J, O'Connell, M, Grover, SR, Heloury, Y, Zacharin, M, Bergman, P, Kimber, C, Brown, J, Webb, N, Hunter, MF, Srinivasan, S, Titmuss, A, Verge, CF, Mowat, D, Smith, G, Smith, J, Ewans, L, Shalhoub, C, Crock, P, Cowell, C, Leong, GM, Ono, M, Lafferty, AR, Huynh, T, Visser, U, Choong, CS, McKenzie, F, Pachter, N, Thompson, EM, Couper, J, Baxendale, A, Gecz, J, Wheeler, BJ, Jefferies, C, MacKenzie, K, Hofman, P, Carter, P, King, RI, Krausz, C, van Ravenswaaij-Arts, CMA, Looijenga, L, Drop, S, Riedl, S, Cools, M, Dawson, A, Juniarto, AZ, Khadilkar, V, Khadilkar, A, Bhatia, V, Vu, CD, Atta, I, Raza, J, Nguyen, TDC, Tran, KH, Harley, V, Koopman, P, Warne, G, Faradz, S, Oshlack, A, Ayers, KL, Sinclair, AH, Eggers, S, Sadedin, S, van den Bergen, JA, Robevska, G, Ohnesorg, T, Hewitt, J, Lambeth, L, Bouty, A, Knarston, IM, Tiong, YT, Cameron, F, Werther, G, Hutson, J, O'Connell, M, Grover, SR, Heloury, Y, Zacharin, M, Bergman, P, Kimber, C, Brown, J, Webb, N, Hunter, MF, Srinivasan, S, Titmuss, A, Verge, CF, Mowat, D, Smith, G, Smith, J, Ewans, L, Shalhoub, C, Crock, P, Cowell, C, Leong, GM, Ono, M, Lafferty, AR, Huynh, T, Visser, U, Choong, CS, McKenzie, F, Pachter, N, Thompson, EM, Couper, J, Baxendale, A, Gecz, J, Wheeler, BJ, Jefferies, C, MacKenzie, K, Hofman, P, Carter, P, King, RI, Krausz, C, van Ravenswaaij-Arts, CMA, Looijenga, L, Drop, S, Riedl, S, Cools, M, Dawson, A, Juniarto, AZ, Khadilkar, V, Khadilkar, A, Bhatia, V, Vu, CD, Atta, I, Raza, J, Nguyen, TDC, Tran, KH, Harley, V, Koopman, P, Warne, G, Faradz, S, Oshlack, A, Ayers, KL, and Sinclair, AH
- Abstract
BACKGROUND: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. RESULTS: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. CONCLUSIONS: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.
- Published
- 2016
15. A duplication in a patient with 46, XX ovo-testicular disorder of sex development refines the SOX9 testis-specific regulatory region to 24 kb.
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Ohnesorg, T., Bergen, J.A., Belluoccio, D., Shankara‐Narayana, N., Kean, A.‐M., Vasilaras, A., Ewans, L., Ayers, K.L., and Sinclair, A.H.
- Subjects
TESTICULAR diseases ,PHENOTYPES ,PATIENTS - Abstract
A custom CGH microarray that covers the SOX9 regulatory region. Log2 ratio scatterplot showing individual data points. Blue box highlights copy number gain with 3′ breakpoint region magnified. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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16. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.
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Chen Y, Dawes R, Kim HC, Ljungdahl A, Stenton SL, Walker S, Lord J, Lemire G, Martin-Geary AC, Ganesh VS, Ma J, Ellingford JM, Delage E, D'Souza EN, Dong S, Adams DR, Allan K, Bakshi M, Baldwin EE, Berger SI, Bernstein JA, Bhatnagar I, Blair E, Brown NJ, Burrage LC, Chapman K, Coman DJ, Compton AG, Cunningham CA, D'Souza P, Danecek P, Délot EC, Dias KR, Elias ER, Elmslie F, Evans CA, Ewans L, Ezell K, Fraser JL, Gallacher L, Genetti CA, Goriely A, Grant CL, Haack T, Higgs JE, Hinch AG, Hurles ME, Kuechler A, Lachlan KL, Lalani SR, Lecoquierre F, Leitão E, Fevre AL, Leventer RJ, Liebelt JE, Lindsay S, Lockhart PJ, Ma AS, Macnamara EF, Mansour S, Maurer TM, Mendez HR, Metcalfe K, Montgomery SB, Moosajee M, Nassogne MC, Neumann S, O'Donoghue M, O'Leary M, Palmer EE, Pattani N, Phillips J, Pitsava G, Pysar R, Rehm HL, Reuter CM, Revencu N, Riess A, Rius R, Rodan L, Roscioli T, Rosenfeld JA, Sachdev R, Shaw-Smith CJ, Simons C, Sisodiya SM, Snell P, St Clair L, Stark Z, Stewart HS, Tan TY, Tan NB, Temple SEL, Thorburn DR, Tifft CJ, Uebergang E, VanNoy GE, Vasudevan P, Vilain E, Viskochil DH, Wedd L, Wheeler MT, White SM, Wojcik M, Wolfe LA, Wolfenson Z, Wright CF, Xiao C, Zocche D, Rubenstein JL, Markenscoff-Papadimitriou E, Fica SM, Baralle D, Depienne C, MacArthur DG, Howson JMM, Sanders SJ, O'Donnell-Luria A, and Whiffin N
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Young Adult, Alleles, Brain growth & development, Brain metabolism, Heterozygote, RNA Splice Sites genetics, Spliceosomes genetics, Syndrome, Rare Diseases genetics, Gene Expression Regulation, Developmental, Mutation, Neurodevelopmental Disorders genetics, RNA, Small Nuclear genetics
- Abstract
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes
1 . Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2 . We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5' splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide., (© 2024. The Author(s).)- Published
- 2024
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17. De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.
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Chen Y, Dawes R, Kim HC, Stenton SL, Walker S, Ljungdahl A, Lord J, Ganesh VS, Ma J, Martin-Geary AC, Lemire G, D'Souza EN, Dong S, Ellingford JM, Adams DR, Allan K, Bakshi M, Baldwin EE, Berger SI, Bernstein JA, Brown NJ, Burrage LC, Chapman K, Compton AG, Cunningham CA, D'Souza P, Délot EC, Dias KR, Elias ER, Evans CA, Ewans L, Ezell K, Fraser JL, Gallacher L, Genetti CA, Grant CL, Haack T, Kuechler A, Lalani SR, Leitão E, Fevre AL, Leventer RJ, Liebelt JE, Lockhart PJ, Ma AS, Macnamara EF, Maurer TM, Mendez HR, Montgomery SB, Nassogne MC, Neumann S, O'Leary M, Palmer EE, Phillips J, Pitsava G, Pysar R, Rehm HL, Reuter CM, Revencu N, Riess A, Rius R, Rodan L, Roscioli T, Rosenfeld JA, Sachdev R, Simons C, Sisodiya SM, Snell P, Clair L, Stark Z, Tan TY, Tan NB, Temple SE, Thorburn DR, Tifft CJ, Uebergang E, VanNoy GE, Vilain E, Viskochil DH, Wedd L, Wheeler MT, White SM, Wojcik M, Wolfe LA, Wolfenson Z, Xiao C, Zocche D, Rubenstein JL, Markenscoff-Papadimitriou E, Fica SM, Baralle D, Depienne C, MacArthur DG, Howson JM, Sanders SJ, O'Donnell-Luria A, and Whiffin N
- Abstract
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes
1 . Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2 . We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals., Competing Interests: Competing interests NW receives research funding from Novo Nordisk and has consulted for ArgoBio studio. SJS receives research funding from BioMarin Pharmaceutical. AODL is on the scientific advisory board for Congenica, was a paid consultant for Tome Biosciences and Ono Pharma USA Inc., and received reagents from PacBio to support rare disease research. HLR has received support from Illumina and Microsoft to support rare disease gene discovery and diagnosis. MHW has consulted for Illumina and Sanofi and received speaking honoraria from Illumina and GeneDx. SBM is an advisor for BioMarin, Myome and Tenaya Therapeutics. SMS has received honoraria for educational events or advisory boards from Angelini Pharma, Biocodex, Eisai, Zogenix/UCB and institutional contributions for advisory boards, educational events or consultancy work from Eisai, Jazz/GW Pharma, Stoke Therapeutics, Takeda, UCB and Zogenix. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. JMMH is a full-time employee of Novo Nordisk and holds shares in Novo Nordisk A/S. DGM is a paid consultant for GlaxoSmithKline, Insitro, and Overtone Therapeutics and receives research support from Microsoft.- Published
- 2024
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18. International Undiagnosed Diseases Programs (UDPs): components and outcomes.
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Curic E, Ewans L, Pysar R, Taylan F, Botto LD, Nordgren A, Gahl W, and Palmer EE
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- Humans, Rare Diseases diagnosis, Rare Diseases genetics, Whole Genome Sequencing, Computational Biology, Exome, Undiagnosed Diseases genetics
- Abstract
Over the last 15 years, Undiagnosed Diseases Programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases, integrating research and clinical care to optimize diagnostic outcomes. This narrative review summarizes the published literature surrounding Undiagnosed Diseases Programs worldwide, including thirteen studies that evaluate outcomes and two commentary papers. Commonalities in the diagnostic and research process of Undiagnosed Diseases Programs are explored through an appraisal of available literature. This exploration allowed for an assessment of the strengths and limitations of each of the six common steps, namely enrollment, comprehensive clinical phenotyping, research diagnostics, data sharing and matchmaking, results, and follow-up. Current literature highlights the potential utility of Undiagnosed Diseases Programs in research diagnostics. Since participants have often had extensive previous genetic studies, research pipelines allow for diagnostic approaches beyond exome or whole genome sequencing, through reanalysis using research-grade bioinformatics tools and multi-omics technologies. The overall diagnostic yield is presented by study, since different selection criteria at enrollment and reporting processes make comparisons challenging and not particularly informative. Nonetheless, diagnostic yield in an undiagnosed cohort reflects the potential of an Undiagnosed Diseases Program. Further comparisons and exploration of the outcomes of Undiagnosed Diseases Programs worldwide will allow for the development and improvement of the diagnostic and research process and in turn improve the value and utility of an Undiagnosed Diseases Program., (© 2023. The Author(s).)
- Published
- 2023
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19. Distinctive Brain Malformations in Zhu-Tokita-Takenouchi-Kim Syndrome.
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Halliday BJ, Baynam G, Ewans L, Greenhalgh L, Leventer RJ, Pilz DT, Sachdev R, Scheffer IE, Markie DM, McGillivray G, Robertson SP, and Mandelstam S
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- Humans, Brain pathology, Magnetic Resonance Imaging, Periventricular Nodular Heterotopia, Brain Diseases pathology, Intellectual Disability pathology
- Abstract
Background and Purpose: Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities. However, these currently identified phenotypic components provide limited guidance in diagnostic situations, due to both the nonspecificity and variability of these features. Here we report a case series of 7 individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome, 5 ascertained by their presentation with the neuronal migration disorder, periventricular nodular heterotopia., Materials and Methods: Individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome were recruited from 2 sources, a high-throughput sequencing study of individuals with periventricular nodular heterotopia or from clinical diagnostic sequencing studies. We analyzed available brain MR images of recruited individuals to characterize periventricular nodular heterotopia distribution and to identify the presence of any additional brain abnormalities., Results: Pathogenic variants in SON , causative of Zhu-Tokita-Takenouchi-Kim syndrome, were identified in 7 individuals. Brain MR images from these individuals were re-analyzed. A characteristic set of imaging anomalies in addition to periventricular nodular heterotopia was identified, including the elongation of the pituitary stalk, cerebellar enlargement with an abnormally shaped posterior fossa, rounding of the caudate nuclei, hippocampal malformations, and cortical anomalies including polymicrogyria or dysgyria., Conclusions: The recurrent neuroradiologic changes identified here represent an opportunity to guide diagnostic formulation of Zhu-Tokita-Takenouchi-Kim syndrome on the basis of brain MR imaging evaluation., (© 2022 by American Journal of Neuroradiology.)
- Published
- 2022
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20. Recommendations for next generation sequencing data reanalysis of unsolved cases with suspected Mendelian disorders: A systematic review and meta-analysis.
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Dai P, Honda A, Ewans L, McGaughran J, Burnett L, Law M, and Phan TG
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- Humans, Exome Sequencing methods, Artificial Intelligence, High-Throughput Nucleotide Sequencing
- Abstract
Purpose: The study aimed to determine the diagnostic yield, optimal timing, and methodology of next generation sequencing data reanalysis in suspected Mendelian disorders., Methods: We conducted a systematic review and meta-analysis of studies that conducted data reanalysis in patients with suspected Mendelian disorders. Random effects model was used to pool the estimated outcome with subgroup analysis stratified by timing, sequencing methodology, sample size, segregation, use of research validation, and artificial intelligence (AI) variant curation tools., Results: A search of PubMed, Embase, Scopus, and Web of Science between 2007 and 2021 yielded 9327 articles, of which 29 were selected. Significant heterogeneity was noted between studies. Reanalysis had an overall diagnostic yield of 0.10 (95% CI = 0.06-0.13). Literature updates accounted for most new diagnoses. Diagnostic yield was higher after 24 months, although this was not statistically significant. Increased diagnoses were obtained with research validation and data sharing. AI-based tools did not adversely affect reanalysis diagnostic rate., Conclusion: Next generation sequencing data reanalysis can improve diagnostic yield. Owing to the heterogeneity of the studies, the optimal time to reanalysis and the impact of AI-based tools could not be determined with confidence. We propose standardized guidelines for future studies to reduce heterogeneity and improve the quality of the conclusions., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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21. MERTK retinopathy: biomarkers assessing vision loss.
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Sakti DH, Cornish EE, Mustafic N, Zaheer A, Retsas S, Rajagopalan S, Chung CW, Ewans L, McCluskey P, Nash BM, Jamieson RV, and Grigg JR
- Subjects
- Adolescent, Adult, Child, Electroretinography, Female, Fluorescein Angiography, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Retina physiopathology, Retinal Pigment Epithelium pathology, Retinitis Pigmentosa diagnostic imaging, Retinitis Pigmentosa physiopathology, Tomography, Optical Coherence, Vision Disorders diagnosis, Vision Disorders physiopathology, Visual Acuity physiology, Visual Field Tests, Visual Fields physiology, Young Adult, Biomarkers, Retinitis Pigmentosa genetics, Vision Disorders genetics, c-Mer Tyrosine Kinase genetics
- Abstract
Purpose: Mer tyrosine kinase-retinitis pigmentosa ( MERTK- RP) causes a primary defect in the retinal pigment epithelium, which subsequently affects rod and cone photoreceptors. The study aims to identify the most appropriate MERTK -RP biomarkers to measure disease progression for deciding the optimum therapeutic trial intervention time., Materials and Methods: Patients' data from baseline (BL) and last follow-up (LFU) were reviewed. Best corrected visual acuity (BCVA), spectral domain-optical coherence tomography (SD-OCT), ultra-widefield fundus autofluorescence (UWF-FAF) patterns, kinetic perimetry (KP), and electroretinography (ERG) parameters were analyzed., Results: Five patients were included with the mean age of 17.7 ± 14.4 years old (6.7-42.3) at BL and mean BCVA follow-up of 8.4 ± 5.1 years. Mean BCVA at BL and LFU were 0.84 ± 0.86 LogMAR and 1.14 ± 0.86 LogMAR, respectively. The BCVA decline rate was 0.05 ± 0.03 LogMAR units/year. Ellipzoid zones (EZ) were measurable in eight eyes with mean BL length of 1293.75 ± 421.07 µm and reduction of 140.95 ± 69.28 µm/year and mean BL CMT of 174.2 ± 37.52 µm with the rate of 11.2 ± 12.77 µm declining/year. Full-field ERG (ffERG) and pattern ERG (pERG) were barely recordable. UWF-FAF showed central macular hyper-autofluorescence (hyperAF). KP (III4e and V4e) was normal in two eyes, restricted nasally in four eyes, superior wedge defect in two eyes and undetectable in two eyes. The four restricted nasally KPs became worse, while the others stayed almost unchanged., Conclusions: This cohort showed early visual loss, moderately rapid EZ reduction and macular hyperAF. EZ, CMT, and BCVA were consistently reduced. Relative rapid decline in these biomarkers reflecting visual function suggests an early and narrow timespan for intervention.
- Published
- 2021
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22. Clinically Responsive Genomic Analysis Pipelines: Elements to Improve Detection Rate and Efficiency.
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Sundercombe SL, Berbic M, Evans CA, Cliffe C, Elakis G, Temple SEL, Selvanathan A, Ewans L, Quayum N, Nixon CY, Dias KR, Lang S, Richards A, Goh S, Wilson M, Mowat D, Sachdev R, Sandaradura S, Walsh M, Farrar MA, Walsh R, Fletcher J, Kirk EP, Teunisse GM, Schofield D, Buckley MF, Zhu Y, and Roscioli T
- Subjects
- Cost-Benefit Analysis, Exome, Genetic Testing economics, Genome, Human, Genomics economics, High-Throughput Nucleotide Sequencing economics, Humans, INDEL Mutation, Phenotype, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Exome Sequencing economics, Genetic Diseases, Inborn genetics, Genetic Testing methods, Genomics methods, Germ-Line Mutation, High-Throughput Nucleotide Sequencing methods, Exome Sequencing methods
- Abstract
Massively parallel sequencing has markedly improved mendelian diagnostic rates. This study assessed the effects of custom alterations to a diagnostic genomic bioinformatic pipeline in response to clinical need and derived practice recommendations relative to diagnostic rates and efficiency. The Genomic Annotation and Interpretation Application (GAIA) bioinformatics pipeline was designed to detect panel, exome, and genome sample integrity and prioritize gene variants in mendelian disorders. Reanalysis of selected negative cases was performed after improvements to the pipeline. GAIA improvements and their effect on sensitivity are described, including addition of a PubMed search for gene-disease associations not in the Online Mendelian Inheritance of Man database, inclusion of a process for calling low-quality variants (known as QPatch), and gene symbol nomenclature consistency checking. The new pipeline increased the diagnostic rate and reduced staff costs, resulting in a saving of US$844.34 per additional diagnosis. Recommendations for genomic analysis pipeline requirements are summarized. Clinically responsive bioinformatics pipeline improvements increase diagnostic sensitivity and increase cost-effectiveness., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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23. A deep intronic SMARCB1 variant associated with schwannomatosis.
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Smith MJ, Bowers NL, Banks C, Coates-Brown R, Morris KA, Ewans L, Wilson M, Pinner J, Bhaskar SS, Cammarata-Scalisi F, Wallace AJ, and Evans DGR
- Subjects
- Adult, Female, Genetic Linkage, Humans, Introns genetics, Neurilemmoma pathology, Neurofibromatoses pathology, Skin Neoplasms pathology, Genetic Predisposition to Disease, Neurilemmoma genetics, Neurofibromatoses genetics, SMARCB1 Protein genetics, Skin Neoplasms genetics
- Published
- 2020
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24. Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.
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Cheng H, Capponi S, Wakeling E, Marchi E, Li Q, Zhao M, Weng C, Stefan PG, Ahlfors H, Kleyner R, Rope A, Lumaka A, Lukusa P, Devriendt K, Vermeesch J, Posey JE, Palmer EE, Murray L, Leon E, Diaz J, Worgan L, Mallawaarachchi A, Vogt J, de Munnik SA, Dreyer L, Baynam G, Ewans L, Stark Z, Lunke S, Gonçalves AR, Soares G, Oliveira J, Fassi E, Willing M, Waugh JL, Faivre L, Riviere JB, Moutton S, Mohammed S, Payne K, Walsh L, Begtrup A, Guillen Sacoto MJ, Douglas G, Alexander N, Buckley MF, Mark PR, Adès LC, Sandaradura SA, Lupski JR, Roscioli T, Agrawal PB, Kline AD, Wang K, Timmers HTM, and Lyon GJ
- Abstract
We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved., (This article is protected by copyright. All rights reserved.)
- Published
- 2019
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25. Silver Russel syndrome in an aboriginal patient from Australia.
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Poulton C, Azmanov D, Atkinson V, Beilby J, Ewans L, Gration D, Dreyer L, Shetty V, Peake C, McCormack E, Palmer R, Lewis B, Dawkins H, Broley S, and Baynam G
- Subjects
- Alleles, Alternative Splicing, Australia, Child, Preschool, Electroencephalography, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Insulin-Like Growth Factor II genetics, Mutation, RNA Splice Sites, Silver-Russell Syndrome diagnosis, Silver-Russell Syndrome genetics
- Abstract
Silver-Russell syndrome (SRS OMIM 180860) is a rare, albeit well-recognized disorder characterized by severe intrauterine and postnatal growth retardation. It remains a clinical diagnosis with a molecular cause identifiable in approximately 60%-70% of patients. We report a 4-year-old Australian Aboriginal girl who was born at 32 weeks gestation with features strongly suggestive of SRS, after extensive investigation she was referred to our undiagnosed disease program (UDP). Genomic sequencing was performed which identified a heterozygous splice site variant in IGF2 which is predicted to be pathogenic by in-silico studies, paternal allelic origin, de novo status, and RNA studies on fibroblasts. We compare clinical findings with reported patients to add to the knowledge base on IGF2 variants and to promote the engagement of other Australian Aboriginal families in genomic medicine., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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26. Painful ovulation in a 46,XX SRY -ve adult male with SOX9 duplication.
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Shankara Narayana N, Kean AM, Ewans L, Ohnesorg T, Ayers KL, Watson G, Vasilaras A, Sinclair AH, Twigg SM, and Handelsman DJ
- Abstract
46,XX disorders of sexual development (DSDs) occur rarely and result from disruptions of the genetic pathways underlying gonadal development and differentiation. We present a case of a young phenotypic male with 46,XX SRY-negative ovotesticular DSD resulting from a duplication upstream of SOX9 presenting with a painful testicular mass resulting from ovulation into an ovotestis. We present a literature review of ovulation in phenotypic men and discuss the role of SRY and SOX9 in testicular development, including the role of SOX9 upstream enhancer region duplication in female-to-male sex reversal., Learning Points: In mammals, the early gonad is bipotent and can differentiate into either a testis or an ovary. SRY is the master switch in testis determination, responsible for differentiation of the bipotent gonad into testis.SRY activates SOX9 gene, SOX9 as a transcription factor is the second major gene involved in male sex determination. SOX9 drives the proliferation of Sertoli cells and activates AMH/MIS repressing the ovary. SOX9 is sufficient to induce testis formation and can substitute for SRY function.Assessing karyotype and then determination of the presence or absence of Mullerian structures are necessary serial investigations in any case of DSD, except for mixed gonadal dysgenesis identified by karyotype alone.Treatment is ideal in a multidisciplinary setting with considerations to genetic (implications to family and reproductive recurrence risk), psychological aspects (sensitive individualized counseling including patient gender identity and preference), endocrinological (hormone replacement), surgical (cosmetic, prophylactic gonadectomy) fertility preservation and reproductive opportunities and metabolic health (cardiovascular and bones).
- Published
- 2017
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27. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort.
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Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T, Hewitt J, Lambeth L, Bouty A, Knarston IM, Tan TY, Cameron F, Werther G, Hutson J, O'Connell M, Grover SR, Heloury Y, Zacharin M, Bergman P, Kimber C, Brown J, Webb N, Hunter MF, Srinivasan S, Titmuss A, Verge CF, Mowat D, Smith G, Smith J, Ewans L, Shalhoub C, Crock P, Cowell C, Leong GM, Ono M, Lafferty AR, Huynh T, Visser U, Choong CS, McKenzie F, Pachter N, Thompson EM, Couper J, Baxendale A, Gecz J, Wheeler BJ, Jefferies C, MacKenzie K, Hofman P, Carter P, King RI, Krausz C, van Ravenswaaij-Arts CM, Looijenga L, Drop S, Riedl S, Cools M, Dawson A, Juniarto AZ, Khadilkar V, Khadilkar A, Bhatia V, Dũng VC, Atta I, Raza J, Thi Diem Chi N, Hao TK, Harley V, Koopman P, Warne G, Faradz S, Oshlack A, Ayers KL, and Sinclair AH
- Subjects
- Cohort Studies, Disorders of Sex Development pathology, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Gonads growth & development, Gonads pathology, Humans, Male, Mutation genetics, Ovary growth & development, Ovary pathology, Pedigree, Phenotype, Testis growth & development, Testis pathology, Chromosome Aberrations, Disorders of Sex Development diagnosis, Disorders of Sex Development genetics, High-Throughput Nucleotide Sequencing
- Abstract
Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously., Results: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management., Conclusions: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.
- Published
- 2016
- Full Text
- View/download PDF
28. Clinical and molecular characterization of the 20q11.2 microdeletion syndrome: six new patients.
- Author
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Jedraszak G, Demeer B, Mathieu-Dramard M, Andrieux J, Receveur A, Weber A, Maye U, Foulds N, Temple IK, Crolla J, Alex-Cordier MP, Sanlaville D, Ewans L, Wilson M, Armstrong R, Clarkson A, Copin H, and Morin G
- Subjects
- Adolescent, Child, Child, Preschool, Chromosome Aberrations, Chromosome Breakpoints, Comparative Genomic Hybridization, Facies, Female, Genetic Association Studies, Humans, Infant, Karyotyping, Male, Syndrome, Young Adult, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Chromosome Deletion, Chromosomes, Human, Pair 20, Phenotype
- Abstract
Interstitial microdeletions of 20q chromosome are rare, only 17 patients have been reported in the literature to date. Among them, only six carried a proximal 20q11.21-q11.23 deletion, with a size ranging from 2.6 to 6.8 Mb. The existence of a 20q11.2 microdeletion syndrome has been proposed, based on five previously reported cases that displayed anomalies of the extremities, intellectual disability, feeding difficulties, craniofacial dysmorphism and variable malformations. To further characterize this syndrome, we report on six new patients with 20q11.2 microdeletions diagnosed by whole-genome array-based comparative genomic hybridization. These patient reports more precisely refined the phenotype and narrowed the minimal critical region involved in this syndrome. Careful clinical assessment confirms the distinctive clinical phenotype. The craniofacial dysmorphism consists of high forehead, frontal bossing, enophthalmos, and midface hypoplasia. We have identified a 1.62 megabase minimal critical region involved in this syndrome encompassing three genes—GDF5, EPB41L1, andSAMHD1—which are strong candidates for different aspects of the phenotype. These results support that 20q11.2 microdeletion syndrome is a new contiguous gene deletion syndrome with a recognizable phenotype., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
29. Upregulation of alpha-synuclein in neurons and glia in inflammatory demyelinating disease.
- Author
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Papadopoulos D, Ewans L, Pham-Dinh D, Knott J, and Reynolds R
- Subjects
- Animals, Encephalomyelitis, Autoimmune, Experimental chemically induced, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Humans, In Situ Hybridization, Mice, Multiple Sclerosis metabolism, Myelin Basic Protein metabolism, Myelin Proteins, Myelin-Associated Glycoprotein immunology, Myelin-Associated Glycoprotein toxicity, Myelin-Oligodendrocyte Glycoprotein, Neuroglia cytology, Neurons cytology, Peripheral Nerves cytology, Peripheral Nerves metabolism, Peripheral Nerves pathology, Rats, Recombinant Proteins immunology, Recombinant Proteins toxicity, Spinal Cord cytology, Spinal Cord metabolism, Spinal Cord pathology, Up-Regulation, alpha-Synuclein genetics, Encephalomyelitis, Autoimmune, Experimental metabolism, Neuroglia metabolism, Neurons metabolism, alpha-Synuclein metabolism
- Abstract
A growing body of evidence suggests that axonal loss and neurodegeneration are responsible for the permanent neurological deficit that typically develops in the course of MS. To investigate the neurodegenerative component of MS pathogenesis, we examined the expression of alpha-synuclein, a protein whose accumulation is common to many neurodegenerative disorders, under conditions of immune-mediated inflammatory demyelination. alpha-Synuclein expression was examined in the spinal cord of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats using immunofluorescence and in situ hybridization and in postmortem tissues from cases of secondary progressive MS using immunohistochemistry. alpha-Synuclein upregulation was detected in neurons and glia in and close by lesions and in normal appearing spinal cord EAE tissue at the protein and mRNA levels. alpha-Synuclein positive neurons and glia appeared early, and their number was maximal during EAE exacerbations, but some expression was maintained throughout the course of EAE. In addition, increased alpha-synuclein expression was detected in neurons and glia in and close to MS lesions. Although the increased expression of alpha-synuclein was detected as a granular cytoplasmic labeling rather than inclusion bodies, this result does suggest that neuronal cell death in immune-mediated demyelinating disease may share some common features with other neurodegenerative conditions.
- Published
- 2006
- Full Text
- View/download PDF
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