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1. Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants

Author

Abdulrasool, Ghusoon, Akesson, Lauren S., Al Eryani, Ghamdan, Al-Shinnag, Mohammad, Arts, Peer, Bagnall, Richard, Baker, Naomi L., Barnett, Christopher, Beecroft, Sarah, Bennetts, Bruce, Berbic, Marina, Beshay, Victoria, Black, Michael, Blackburn, Jim, Blombery, Piers, Boggs, Kirsten, Bournazos, Adam M., Branford, Susan, Breen, Jimmy, Brown, Natasha J., Bryen, Samantha J., Burnett, Leslie, Canson, Daffodil, Cheong, Pak, Chew, Edward, Chong, Belinda, Christodoulou, John, Chung, Seo-Kyung, Clark, Mike, Cliffe, Corrina, Cole, Melissa, Collins, Felicity, Compton, Alison, Cooper, Antony, Cooper, Sandra T., Corbett, Mark, Cowley, Mark, Davis, Mark R., Delatycki, Martin, Dudding, Tracy, Edwards, Matthew, Eggers, Stefanie, Ewans, Lisa J., Eyras, Eduardo, Faiz, Fathimath, Fernandez, Miriam Fanjul, Fellowes, Andrew, Fennell, Andrew, Field, Michael, Fleischer, Ron, Folland, Chiara, Fox, Lucy, Freckmann, Mary-Louise, Gaff, Clara, Galea, Melanie, Ghaoui, Roula, Goel, Himanshu, Gornanitis, Ilias, Ha, Thuong, Hanna, Bernadette, Harraway, James, Hayashi, Rippei, Hayes, Ian, Henderson, Alex, Hesson, Luke, Heyer, Erin, Hildebrand, Michael, Hipwell, Michael, Ho, Gladys, Horton, Ari E., Hoskins, Cass, Hunter, Matthew F., Jackson, Matilda, James, Paul, Jones, Kristi J., Wong, Justin Jong-Leong, Josephi-Taylor, Sarah, Joshi, Himanshu, Kassahn, Karin, Kaub, Peter, Kevin, Lucy, Kirk, Edwin, Krzesinski, Emma, Kumble, Smitha, Kummerfeld, Sarah, Laing, Nigel, Lau, Chiyan, Lee, Eric, Leighton, Sarah, Lundie, Ben, Lunke, Sebastian, Mallawaarachchi, Amali, Mayoh, Chelsea, McGaughran, Julie, McLean, Alison, McPhillips, Mary, Meldrum, Cliff, Middleton, Edwina, Milnes, Di, Mina, Kym, Mowat, David, Nisselle, Amy, Oates, Emily, Oshlack, Alicia, Palmer, Elizabeth E., Parasivam, Gayathri, Parsons, Michael, Patel, Chirag, Pinner, Jason R., Quinn, Michael, Rasko, John, Ravenscroft, Gina, Ravine, Anja, Recsei, Krista, Regan, Matthew, Rehn, Jacqueline, Riley, Lisa G., Robertson, Stephen, Ronan, Anne, Roscioli, Tony, Ryland, Georgina, Sadedin, Simon, Sandaradura, Sarah A., Schreiber, Andreas, Scott, Hamish, Scott, Rodney, Semsarian, Christopher, Simons, Cas, Singer, Emma, Smith, Janine M., Smyth, Renee, Spurdle, Amanda, Stark, Zornitza, Sullivan, Patricia, Sundercombe, Samantha, Tan, Tiong Y., Tchan, Michel C., Thompson, Bryony A., Thorburn, David, Toubia, John, Trent, Ronald, Tudini, Emma, Voneague, Irina, Waddell, Leigh, Walker, Logan, Wallis, Mathew, Warnock, Nick, Weatheritt, Robert, White, Deborah, White, Susan M., Williams, Mark G., Wilson, Meredith J., Winship, Ingrid, Worgan, Lisa, Wright, Dale C., Wu, Kathy, Yeung, Alison, Ziolowski, Andrew, Bommireddipalli, Shobhana, Ades, Lesley, Alexander, Stephen I., Archibald, Alison D., Balasubramaniam, Shanti, Berman, Yemima, Bojadzieva, Jasmina, Buckley, Michael F., Dawes, Ruebena, Donaldson, Liz, Downie, Lilian, Edwards, Caitlin, Engel, Amanda, Gallacher, Lyndon, Gear, Russell, Goh, Shuxiang, Goodwin, Linda, Higgins, Megan, Hopper, Bruce K., Huq, Aamira J., Kumar, Kishore R., Lemckert, Frances, Leventer, Richard J., Lindsey-Temple, Suzanna E., Ma, Alan, Macaskill, Steven, Marty, Melanie, Marum, Justine E., McCarthy, Hugh J., Menezes, Manoj P., Mohammad, Shekeeb, Niaz, Aram, Patel, Shilpan G., Phelan, Dean, Rajagopalan, Sulekha, Rodgers, Jonathan, Rodrigues, Miriam, Roxburgh, Richard H., Sachdev, Rani, Samarasekera, Ruvishani, Savva, Elena, Schindler, Tim, Shah, Margit, Sinnerbrink, Ingrid B., Smith, Richard J., Springer, Amanda, Strom, Samuel P., Sue, Carolyn M., Tan, Kenneth, Tantsis, Esther, Trainer, Alison H., van Spaendonck-Zwarts, Karin, Walsh, Rebecca, Warwick, Linda, White, Stephanie, Wong, Wui Kwan, Yap, Patrick, and Young, Helen

Published
2022
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2. A cost-effectiveness analysis of genomic sequencing in a prospective versus historical cohort of complex pediatric patients

Author

Yeung, Alison, Tan, Natalie B., Tan, Tiong Y., Stark, Zornitza, Brown, Natasha, Hunter, Matthew F., Delatycki, Martin, Stutterd, Chloe, Savarirayan, Ravi, Mcgillivray, George, Stapleton, Rachel, Kumble, Smitha, Downie, Lilian, Regan, Matthew, Lunke, Sebastian, Chong, Belinda, Phelan, Dean, Brett, Gemma R., Jarmolowicz, Anna, Prawer, Yael, Valente, Giulia, Smagarinsky, Yana, Martyn, Melissa, McEwan, Callum, Goranitis, Ilias, Gaff, Clara, and White, Susan M.

Published
2020
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3. Meeting the challenges of implementing rapid genomic testing in acute pediatric care

Author

Stark, Zornitza, Lunke, Sebastian, Brett, Gemma R., Tan, Natalie B., Stapleton, Rachel, Kumble, Smitha, Yeung, Alison, Phelan, Dean G., Chong, Belinda, Fanjul-Fernandez, Miriam, Marum, Justine E., Hunter, Matthew, Jarmolowicz, Anna, Prawer, Yael, Riseley, Jessica R., Regan, Matthew, Elliott, Justine, Martyn, Melissa, Best, Stephanie, Tan, Tiong Y., Gaff, Clara L., and White, Susan M.

Published
2018
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5. Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

Author

Lunke, Sebastian, Eggers, Stefanie, Wilson, Meredith, Patel, Chirag, Barnett, Christopher P., Pinner, Jason, Sandaradura, Sarah A., Buckley, Michael F., Krzesinski, Emma I., de Silva, Michelle G., Brett, Gemma R., Boggs, Kirsten, Mowat, David, Kirk, Edwin P., Adès, Lesley C., Akesson, Lauren S., Amor, David J., Ayres, Samantha, Baxendale, Anne, Borrie, Sarah, Bray, Alessandra, Brown, Natasha J., Chan, Cheng Yee, Chong, Belinda, Cliffe, Corrina, Delatycki, Martin B., Edwards, Matthew, Elakis, George, Fahey, Michael C., Fennell, Andrew, Fowles, Lindsay, Gallacher, Lyndon, Higgins, Megan, Howell, Katherine B., Hunt, Lauren, Hunter, Matthew F., Jones, Kristi J., King, Sarah, Kumble, Smitha, Lang, Sarah, Le Moing, Maelle, Ma, Alan, Phelan, Dean, Quinn, Michael C. J., Richards, Anna, Richmond, Christopher M., Riseley, Jessica, Rodgers, Jonathan, Sachdev, Rani, Sadedin, Simon, Schlapbach, Luregn J., Smith, Janine, Springer, Amanda, Tan, Natalie B., Tan, Tiong Y., Temple, Suzanna L., Theda, Christiane, Vasudevan, Anand, White, Susan M., Yeung, Alison, Zhu, Ying, Martyn, Melissa, Best, Stephanie, Roscioli, Tony, Christodoulou, John, and Stark, Zornitza

Published
2020
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8. The diverse pleiotropic effects of spliceosomal protein PUF60 : A case series of Verheij syndrome

Author

Fennell, Andrew Paul, primary, Baxter, Anne Elizabeth, additional, Berkovic, Samuel Frank, additional, Ellaway, Carolyn Jane, additional, Forwood, Caitlin, additional, Hildebrand, Michael Stephen, additional, Kumble, Smitha, additional, McKeown, Colina, additional, Mowat, David, additional, Poke, Gemma, additional, Rajagopalan, Sulekha, additional, Regan, Brigid M., additional, Scheffer, Ingrid Eileen, additional, Stark, Zornitza, additional, Stutterd, Chloe Alice, additional, Tan, Tiong Yang, additional, Wilkins, Ella Jane, additional, Yeung, Alison, additional, and Hunter, Matthew Frank, additional

Published
2022
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9. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Author

Kumble, Smitha and Kumble, Smitha

Abstract

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

Published
2022

11. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Author

Kumble, Smitha, Levy, Amanda, Punetha, Jaya, Gao, Hua, Ah Mew, Nicholas, Anyane-Yeboa, Kwame, Benke, Paul, Berger, Sara, Bjerglund, Lise, Campos-Xavier, Belinda, Ciliberto, Michael, Cohen, Julie, Comi, Anne, Curry, Cynthia, Damaj, Lena, Denommé-Pichon, Anne-Sophie, Emrick, Lisa, Faivre, Laurence, Fasano, Mary Beth, Fiévet, Alice, Finkel, Richard, García-Miñaúr, Sixto, Gerard, Amanda, Gomez-Puertas, Paulino, Guillen Sacoto, Maria, Hoffman, Trevor, Howard, Lillian, Iglesias, Alejandro, Izumi, Kosuke, Larson, Austin, Leiber, Anja, Lozano, Reymundo, Marcos-Alcalde, Iñigo, Mintz, Cassie, Mullegama, Sureni, Møller, Rikke, Odent, Sylvie, Oppermann, Henry, Ostergaard, Elsebet, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Paulson, Anna, Platzer, Konrad, Posey, Jennifer, Potocki, Lorraine, Revah-Politi, Anya, Rio, Marlene, Ritter, Alyssa, Robinson, Scott, Rosenfeld, Jill, Santos-Simarro, Fernando, Anyane‐Yeboa, Kwame, Campos‐Xavier, Belinda, Denommé‐Pichon, Anne‐Sophie, García‐Miñaúr, Sixto, Gomez‐Puertas, Paulino, Marcos‐Alcalde, Iñigo, Pacio‐Míguez, Marta, Palomares‐Bralo, Maria, Revah‐Politi, Anya, Santos‐Simarro, Fernando, Sombra, Sérgio Sousa, Wéber, Mathys, Xie, Yili, Chung, Wendy K., Brown, Natasha, Tümer, Zeynep, Murdoch Children's Research Institute (MCRI), Copenhagen University Hospital, Baylor College of Medicine (BCM), Baylor University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), CHU Pontchaillou [Rennes], Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Institut Gustave Roussy (IGR), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CIBER de Enfermedades Raras (CIBERER), GeneDx [Gaithersburg, MD, USA], Columbia University Irving Medical Center (CUIMC), University of Melbourne, University of Copenhagen = Københavns Universitet (KU), Spanish Ministry of Science / State Research Agency projects. Grant Numbers: DTS20-00024, RTC-2017-6494-1, RTI2018-094434-B-I00 SFARI and JPB Foundation, Raregenomics network, financed by the Consejería de Educación de la C. de Madrid. Grant Number: S2017 / BMD-3721, European Comission JPIAMR projects CONNECT and AEPIC, National Center for Advancing Translational Sciences, National Institutes of Health. Grant Number: UL1TR001873, National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI). Grant Number: UM1 HG006542 Undiagnosed Diseases Network, European Social Fund, Rashid Family Fund, NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. Grant Number: U01HG007709, ISCIII, Ministerio de Ciencia e Innovación. Grant Number: PI19/01681, Baylor Hopkins Center for Mendelian Genomics. Grant Numbers: NHGRI K08 HG008986, NHGRI/NLHBI UM1 HG006542, Centro Portugal Regional Operational Programme (CENTRO 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Grant Number: CENTRO-01-0247-FEDER-017800, Département de biologie et pathologie médicales [Gustave Roussy], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and University of Copenhagen = Københavns Universitet (UCPH)

Subjects
Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Dwarfism, Biology, Bioinformatics, Weight Gain, Short stature, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Neuroimaging, Seizures, variable expressivity, Intellectual disability, Genetics, medicine, Missense mutation, Humans, QRICH1, hypotonia, Genetics (clinical), 030304 developmental biology, 0303 health sciences, medicine.disease, Hypotonia, short stature, Scoliosis, variant, Autism spectrum disorder, Neurodevelopmental Disorders, intellectual disability, Muscle Hypotonia, medicine.symptom, 030217 neurology & neurosurgery
Abstract

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability. The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum (ER) stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n=38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/intellectual disability (71%), non-specific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity. This article is protected by copyright. All rights reserved.

Published
2021
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12. Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants

Author

Bournazos, Adam M., primary, Riley, Lisa G., additional, Bommireddipalli, Shobhana, additional, Ades, Lesley, additional, Akesson, Lauren S., additional, Al-Shinnag, Mohammad, additional, Alexander, Stephen I., additional, Archibald, Alison D., additional, Balasubramaniam, Shanti, additional, Berman, Yemima, additional, Beshay, Victoria, additional, Boggs, Kirsten, additional, Bojadzieva, Jasmina, additional, Brown, Natasha J., additional, Bryen, Samantha J., additional, Buckley, Michael F., additional, Chong, Belinda, additional, Davis, Mark R., additional, Dawes, Ruebena, additional, Delatycki, Martin, additional, Donaldson, Liz, additional, Downie, Lilian, additional, Edwards, Caitlin, additional, Edwards, Matthew, additional, Engel, Amanda, additional, Ewans, Lisa J., additional, Faiz, Fathimath, additional, Fennell, Andrew, additional, Field, Michael, additional, Freckmann, Mary-Louise, additional, Gallacher, Lyndon, additional, Gear, Russell, additional, Goel, Himanshu, additional, Goh, Shuxiang, additional, Goodwin, Linda, additional, Hanna, Bernadette, additional, Harraway, James, additional, Higgins, Megan, additional, Ho, Gladys, additional, Hopper, Bruce K., additional, Horton, Ari E., additional, Hunter, Matthew F., additional, Huq, Aamira J., additional, Josephi-Taylor, Sarah, additional, Joshi, Himanshu, additional, Kirk, Edwin, additional, Krzesinski, Emma, additional, Kumar, Kishore R., additional, Lemckert, Frances, additional, Leventer, Richard J., additional, Lindsey-Temple, Suzanna E., additional, Lunke, Sebastian, additional, Ma, Alan, additional, Macaskill, Steven, additional, Mallawaarachchi, Amali, additional, Marty, Melanie, additional, Marum, Justine E., additional, McCarthy, Hugh J., additional, Menezes, Manoj P., additional, McLean, Alison, additional, Milnes, Di, additional, Mohammad, Shekeeb, additional, Mowat, David, additional, Niaz, Aram, additional, Palmer, Elizabeth E., additional, Patel, Chirag, additional, Patel, Shilpan G., additional, Phelan, Dean, additional, Pinner, Jason R., additional, Rajagopalan, Sulekha, additional, Regan, Matthew, additional, Rodgers, Jonathan, additional, Rodrigues, Miriam, additional, Roxburgh, Richard H., additional, Sachdev, Rani, additional, Roscioli, Tony, additional, Samarasekera, Ruvishani, additional, Sandaradura, Sarah A., additional, Savva, Elena, additional, Schindler, Tim, additional, Shah, Margit, additional, Sinnerbrink, Ingrid B., additional, Smith, Janine M., additional, Smith, Richard J., additional, Springer, Amanda, additional, Stark, Zornitza, additional, Strom, Samuel P., additional, Sue, Carolyn M., additional, Tan, Kenneth, additional, Tan, Tiong Y., additional, Tantsis, Esther, additional, Tchan, Michel C., additional, Thompson, Bryony A., additional, Trainer, Alison H., additional, van Spaendonck-Zwarts, Karin, additional, Walsh, Rebecca, additional, Warwick, Linda, additional, White, Stephanie, additional, White, Susan M., additional, Williams, Mark G., additional, Wilson, Meredith J., additional, Wong, Wui Kwan, additional, Wright, Dale C., additional, Yap, Patrick, additional, Yeung, Alison, additional, Young, Helen, additional, Jones, Kristi J., additional, Bennetts, Bruce, additional, Cooper, Sandra T., additional, Abdulrasool, Ghusoon, additional, Al Eryani, Ghamdan, additional, Arts, Peer, additional, Bagnall, Richard, additional, Baker, Naomi L., additional, Barnett, Christopher, additional, Beecroft, Sarah, additional, Berbic, Marina, additional, Black, Michael, additional, Blackburn, Jim, additional, Blombery, Piers, additional, Bournazos, Adam M., additional, Branford, Susan, additional, Breen, Jimmy, additional, Burnett, Leslie, additional, Canson, Daffodil, additional, Cheong, Pak, additional, Chew, Edward, additional, Christodoulou, John, additional, Chung, Seo-Kyung, additional, Clark, Mike, additional, Cliffe, Corrina, additional, Cole, Melissa, additional, Collins, Felicity, additional, Compton, Alison, additional, Cooper, Antony, additional, Corbett, Mark, additional, Cowley, Mark, additional, Dudding, Tracy, additional, Eggers, Stefanie, additional, Eyras, Eduardo, additional, Fernandez, Miriam Fanjul, additional, Fellowes, Andrew, additional, Fleischer, Ron, additional, Folland, Chiara, additional, Fox, Lucy, additional, Gaff, Clara, additional, Galea, Melanie, additional, Ghaoui, Roula, additional, Gornanitis, Ilias, additional, Ha, Thuong, additional, Hayashi, Rippei, additional, Hayes, Ian, additional, Henderson, Alex, additional, Hesson, Luke, additional, Heyer, Erin, additional, Hildebrand, Michael, additional, Hipwell, Michael, additional, Hoskins, Cass, additional, Jackson, Matilda, additional, James, Paul, additional, Wong, Justin Jong-Leong, additional, Kassahn, Karin, additional, Kaub, Peter, additional, Kevin, Lucy, additional, Kumble, Smitha, additional, Kummerfeld, Sarah, additional, Laing, Nigel, additional, Lau, Chiyan, additional, Lee, Eric, additional, Leighton, Sarah, additional, Lundie, Ben, additional, Mayoh, Chelsea, additional, McGaughran, Julie, additional, McPhillips, Mary, additional, Meldrum, Cliff, additional, Middleton, Edwina, additional, Mina, Kym, additional, Nisselle, Amy, additional, Oates, Emily, additional, Oshlack, Alicia, additional, Parasivam, Gayathri, additional, Parsons, Michael, additional, Quinn, Michael, additional, Rasko, John, additional, Ravenscroft, Gina, additional, Ravine, Anja, additional, Recsei, Krista, additional, Rehn, Jacqueline, additional, Robertson, Stephen, additional, Ronan, Anne, additional, Ryland, Georgina, additional, Sadedin, Simon, additional, Schreiber, Andreas, additional, Scott, Hamish, additional, Scott, Rodney, additional, Semsarian, Christopher, additional, Simons, Cas, additional, Singer, Emma, additional, Smyth, Renee, additional, Spurdle, Amanda, additional, Sullivan, Patricia, additional, Sundercombe, Samantha, additional, Thorburn, David, additional, Toubia, John, additional, Trent, Ronald, additional, Tudini, Emma, additional, Voneague, Irina, additional, Waddell, Leigh, additional, Walker, Logan, additional, Wallis, Mathew, additional, Warnock, Nick, additional, Weatheritt, Robert, additional, White, Deborah, additional, Winship, Ingrid, additional, Worgan, Lisa, additional, Wu, Kathy, additional, and Ziolowski, Andrew, additional

Published
2022
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14. Rapid genomic testing in acute paediatric care: Is it worth the trouble?

Author

Stark, Zornitza, primary, Lunke, Sebastian, additional, Brett, Gemma R., additional, Tan, Natalie B., additional, Stapleton, Rachel, additional, Kumble, Smitha, additional, Yeung, Alison, additional, Phelan, Dean G., additional, Chong, Belinda, additional, Fernandez, Miriam Fanjul, additional, Marum, Justine E., additional, Hunter, Matthew, additional, Jarmolowicz, Anna, additional, Prawer, Yael, additional, Riseley, Jessica R., additional, Regan, Matthew, additional, Elliott, Justine, additional, Martyn, Melissa, additional, Best, Stephanie, additional, Tan, Tiong Y., additional, Gaff, Clara L., additional, and White, Susan M., additional

Published
2018
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16. Colour and spectral reflectance of stools from normal neonatal babies.

Author

Griffin, Lewis D., Sutcliffe, Alastair G., Bradbury, Kimberley, Kumble, Smitha, Mylonas, Dimitris, and Baker, Alastair

Subjects
SPECTRAL reflectance, FECES
Abstract

Data is presented on the colour and spectral reflectances of stool samples from healthy young infants (mean age 6 days). The range of spectral reflectances is well described by a pigment mixture model with three components-a pale component corresponding to partially digested milk fats, a yellow component corresponding to bilirubin breakdown products, and a dark component corresponding to meconium and bilirubin. Most stools were tan, beige or olive but white, grey and light grey were also observed. © 2014 Wiley Periodicals, Inc. Col Res Appl, 40, 585-591, 2015 [ABSTRACT FROM AUTHOR]

Published
2015
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18. Erythromelalgia caused by the missense mutation p.Arg220Pro in an alternatively spliced exon of SCN9A (NaV1.7).

Author

Deuis JR, Kumble S, Keramidas A, Ragnarsson L, Simons C, Pais L, White SM, and Vetter I

Subjects
Humans, Mutation, Missense genetics, NAV1.7 Voltage-Gated Sodium Channel genetics, Pain genetics, Mutation, Exons genetics, Erythromelalgia genetics
Abstract

Erythromelalgia (EM), is a familial pain syndrome characterized by episodic 'burning' pain, warmth, and erythema. EM is caused by monoallelic variants in SCN9A, which encodes the voltage-gated sodium channel (NaV) NaV1.7. Over 25 different SCN9A mutations attributed to EM have been described to date, all identified in the SCN9A transcript utilizing exon 6N. Here we report a novel SCN9A missense variant identified in seven related individuals with stereotypic episodes of bilateral lower limb pain presenting in childhood. The variant, XM_011511617.3:c.659G>C;p.(Arg220Pro), resides in the exon 6A of SCN9A, an exon previously shown to be selectively incorporated by developmentally regulated alternative splicing. The mutation is located in the voltage-sensing S4 segment of domain I, which is important for regulating channel activation. Functional analysis showed the p.Arg220Pro mutation altered voltage-dependent activation and delayed channel inactivation, consistent with a NaV1.7 gain-of-function molecular phenotype. These results demonstrate that alternatively spliced isoforms of SCN9A should be included in all genomic testing of EM., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2024
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19. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder.

Author

Kumble S, Levy AM, Punetha J, Gao H, Ah Mew N, Anyane-Yeboa K, Benke PJ, Berger SM, Bjerglund L, Campos-Xavier B, Ciliberto M, Cohen JS, Comi AM, Curry C, Damaj L, Denommé-Pichon AS, Emrick L, Faivre L, Fasano MB, Fiévet A, Finkel RS, García-Miñaúr S, Gerard A, Gomez-Puertas P, Guillen Sacoto MJ, Hoffman TL, Howard L, Iglesias AD, Izumi K, Larson A, Leiber A, Lozano R, Marcos-Alcalde I, Mintz CS, Mullegama SV, Møller RS, Odent S, Oppermann H, Ostergaard E, Pacio-Míguez M, Palomares-Bralo M, Parikh S, Paulson AM, Platzer K, Posey JE, Potocki L, Revah-Politi A, Rio M, Ritter AL, Robinson S, Rosenfeld JA, Santos-Simarro F, Sousa SB, Wéber M, Xie Y, Chung WK, Brown NJ, and Tümer Z

Subjects
Humans, Muscle Hypotonia, Seizures, Weight Gain, Autism Spectrum Disorder genetics, Dwarfism, Intellectual Disability genetics, Neurodevelopmental Disorders genetics, Scoliosis
Abstract

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity., (© 2021 Wiley Periodicals LLC.)

Published
2022
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20. Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System.

Author

Lunke S, Eggers S, Wilson M, Patel C, Barnett CP, Pinner J, Sandaradura SA, Buckley MF, Krzesinski EI, de Silva MG, Brett GR, Boggs K, Mowat D, Kirk EP, Adès LC, Akesson LS, Amor DJ, Ayres S, Baxendale A, Borrie S, Bray A, Brown NJ, Chan CY, Chong B, Cliffe C, Delatycki MB, Edwards M, Elakis G, Fahey MC, Fennell A, Fowles L, Gallacher L, Higgins M, Howell KB, Hunt L, Hunter MF, Jones KJ, King S, Kumble S, Lang S, Le Moing M, Ma A, Phelan D, Quinn MCJ, Richards A, Richmond CM, Riseley J, Rodgers J, Sachdev R, Sadedin S, Schlapbach LJ, Smith J, Springer A, Tan NB, Tan TY, Temple SL, Theda C, Vasudevan A, White SM, Yeung A, Zhu Y, Martyn M, Best S, Roscioli T, Christodoulou J, and Stark Z

Subjects
Australia, Child, Child, Preschool, Feasibility Studies, Female, Genetic Diseases, Inborn diagnosis, Humans, Infant, Infant, Newborn, Male, National Health Programs, Prospective Studies, Time Factors, Critical Illness, Genetic Diseases, Inborn genetics, Genetic Testing methods, Exome Sequencing methods
Abstract

Importance: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems., Objective: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system., Design, Setting, and Participants: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption., Exposures: Ultra-rapid exome sequencing., Main Outcomes and Measures: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge., Results: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%)., Conclusions and Relevance: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.

Published
2020
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21. Chondrodysplasia Punctata 2, X-Linked

Author

Kumble S, Savarirayan R, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, and Amemiya A

Abstract

Clinical Characteristics: The findings in X-linked chondrodysplasia punctata 2 (CDPX2) range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including females with no recognizable physical abnormalities. At least 95% of liveborn individuals with CDPX2 are female. Characteristic features include growth deficiency; distinctive craniofacial appearance; chondrodysplasia punctata (stippling of the epiphyses of the long bones, vertebrae, trachea, and distal ends of the ribs); often asymmetric rhizomelic shortening of limbs; scoliosis; linear or blotchy scaling ichthyosis in the newborn; later appearance of linear or whorled atrophic patches involving hair follicles (follicular atrophoderma); coarse hair with scarring alopecia; and cataracts., Diagnosis/testing: The diagnosis of CDPX2 is established in a female proband with: typical clinical findings, increased concentration of 8(9)-cholestenol and 8-dehydrocholesterol in plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts; and/or a heterozygous pathogenic variant in EBP identified by molecular genetic testing. The diagnosis of CDPX2 is established in a male proband with: typical clinical findings, increased concentration of 8(9)-cholestenol and 8-dehydrocholesterol in plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts; and/or a hemizygous pathogenic variant in EBP identified by molecular genetic testing., Management: Treatment of manifestations: Treatment is symptomatic and individualized. For individuals with typical CDPX2 diagnosed in the newborn period, the following are appropriate: orthopedic management of leg length discrepancy; frequent assessment of kyphoscoliosis; management of respiratory compromise as per pulmonologist; dermatologic management with emollients and keratolytics; sun protection; cataract extraction and correction of vision; standard interventions for hearing loss and hydronephrosis; family support. Surveillance: Regular orthopedic evaluations to monitor kyphoscoliosis, joint problems, and any leg length discrepancy; follow up with a dermatologist; regular follow up of ophthalmologic abnormalities; audiology evaluations as indicated; monitor hydronephrosis if present. Agents/circumstances to avoid: Prolonged sun exposure for individuals with ichthyosis, who are at risk of dehydration secondary to overheating. Use of emollients (which are oil based) and direct sun exposure can lead to sunburn., Genetic Counseling: CDPX2 is inherited in an X-linked manner with early gestational male lethality. Women with an EBP germline pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child: EBP pathogenic variants in sons are usually lethal; daughters will have a range of possible phenotypic expression. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population. If the pathogenic variant cannot be detected in the DNA extracted from the leukocytes of either parent of the proband, three possible explanations are germline mosaicism, somatic mosaicism, or a de novo pathogenic variant in the proband. Prenatal diagnosis for pregnancies at increased risk is possible if the family-specific pathogenic variant is known., (Copyright © 1993-2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.)

Published
1993

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