Browsing by Author "Zackai, Elaine"

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    Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation
    (Elsevier, 2019-03) Koczkowska, Magdalena; Callens, Tom; Gomes, Alicia; Sharp, Angela; Chen, Yunjia; Hicks, Alesha D.; Aylsworth, Arthur S.; Azizi, Amedeo A.; Basel, Donald G.; Bellus, Gary; Bird, Lynne M.; Blazo, Maria A.; Burke, Leah W.; Cannon, Ashley; Collins, Felicity; DeFilippo, Colette; Denayer, Ellen; Digilio, Maria C.; Dills, Shelley K.; Dosa, Laura; Greenwood, Robert S.; Griffis, Cristin; Gupta, Punita; Hachen, Rachel K.; Hernández-Chico, Concepción; Janssens, Sandra; Jones, Kristi J.; Jordan, Justin T.; Kannu, Peter; Korf, Bruce R.; Lewis, Andrea M.; Listernick, Robert H.; Lonardo, Fortunato; Mahoney, Maurice J.; Ojeda, Mayra Martinez; McDonald, Marie T.; McDougall, Carey; Mendelsohn, Nancy; Miller, David T.; Mori, Mari; Oostenbrink, Rianne; Perreault, Sebastién; Pierpont, Mary Ella; Piscopo, Carmelo; Pond, Dinel A.; Randolph, Linda M.; Rauen, Katherine A.; Rednam, Surya; Rutledge, S. Lane; Saletti, Veronica; Schaefer, G. Bradley; Schorry, Elizabeth K.; Scott, Daryl A.; Shugar, Andrea; Siqveland, Elizabeth; Starr, Lois J.; Syed, Ashraf; Trapane, Pamela L.; Ullrich, Nicole J.; Wakefield, Emily G.; Walsh, Laurence E.; Wangler, Michael F.; Zackai, Elaine; Claes, Kathleen B.M.; Wimmer, Katharina; van Minkelen, Rick; De Luca, Alessandro; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine M.; Neurology, School of Medicine
    Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofi- bromas. We did not identify any complications, such as sympto-matic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofi-bromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
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    A dyadic approach to the delineation of diagnostic entities in clinical genomics
    (Cell Press, 2021-01-07) Biesecker, Leslie G.; Adam, Margaret P.; Alkuraya, Fowzan S.; Amemiya, Anne R.; Bamshad, Michael J.; Beck, Anita E.; Bennett, James T.; Bird, Lynne M.; Carey, John C.; Chung, Brian; Clark, Robin D.; Cox, Timothy C.; Curry, Cynthia; Palko Dinulos, Mary Beth; Dobyns, William B.; Giampietro, Philip F.; Girisha, Katta M.; Glass, Ian A.; Graham, John M., Jr.; Gripp, Karen W.; Haldeman-Englert, Chad R.; Hall, Bryan D.; Innes, A. Micheil; Kalish, Jennifer M.; Keppler-Noreuil, Kim M.; Kosaki, Kenjiro; Kozel, Beth A.; Mirzaa, Ghayda M.; Mulvihill, John J.; Nowaczyk, Malgorzata J.M.; Pagon, Roberta A.; Retterer, Kyle; Rope, Alan F.; Sanchez-Lara, Pedro A.; Seaver, Laurie H.; Shieh, Joseph T.; Slavotinek, Anne M.; Sobering, Andrew K.; Stevens, Cathy A.; Stevenson, David A.; Tan, Tiong Yang; Tan, Wen-Hann; Tsai, Anne C.; Weaver, David D.; Williams, Marc S.; Zackai, Elaine; Zarate, Yuri A.; Medical and Molecular Genetics, School of Medicine
    The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
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    Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation
    (Springer Nature, 2019-04) Koczkowska, Magdalena; Callens, Tom; Gomes, Alicia; Sharp, Angela; Chen, Yunjia; Hicks, Alesha D.; Aylsworth, Arthur S.; Azizi, Amedeo A.; Basel, Donald G.; Bellus, Gary; Bird, Lynne M.; Blazo, Maria A.; Burke, Leah W.; Cannon, Ashley; Collins, Felicity; DeFilippo, Colette; Denayer, Ellen; Digilio, Maria C.; Dills, Shelley K.; Dosa, Laura; Greenwood, Robert S.; Griffis, Cristin; Gupta, Punita; Hachen, Rachel K.; Hernández-Chico, Concepción; Janssens, Sandra; Jones, Kristi J.; Jordan, Justin T.; Kannu, Peter; Korf, Bruce R.; Lewis, Andrea M.; Listernick, Robert H.; Lonardo, Fortunato; Mahoney, Maurice J.; Ojeda, Mayra Martinez; McDonald, Marie T.; McDougall, Carey; Mendelsohn, Nancy; Miller, David T.; Mori, Mari; Oostenbrink, Rianne; Perreault, Sebastién; Pierpont, Mary Ella; Piscopo, Carmelo; Pond, Dinel A.; Randolph, Linda M.; Rauen, Katherine A.; Rednam, Surya; Rutledge, S. Lane; Saletti, Veronica; Schaefer, G. Bradley; Schorry, Elizabeth K.; Scott, Daryl A.; Shugar, Andrea; Siqveland, Elizabeth; Starr, Lois J.; Syed, Ashraf; Trapane, Pamela L.; Ullrich, Nicole J.; Wakefield, Emily G.; Walsh, Laurence E.; Wangler, Michael F.; Zackai, Elaine; Claes, Kathleen B. M.; Wimmer, Katharina; van Minkelen, Rick; De Luca, Alessandro; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine M.; Neurology, School of Medicine
    PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
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    Response to Hamosh et al
    (Elsevier, 2021) Biesecker, Leslie G.; Adam, Margaret P.; Alkuraya, Fowzan S.; Amemiya, Anne R.; Bamshad, Michael J.; Beck, Anita E.; Bennett, James T.; Bird, Lynne M.; Carey, John C.; Chung, Brian; Clark, Robin D.; Cox, Timothy C.; Curry, Cynthia; Dinulos, Mary Beth Palko; Dobyns, William B.; Giampietro, Philip F.; Girisha, Katta M.; Glass, Ian A.; Graham, John M., Jr.; Gripp, Karen W.; Haldeman-Englert, Chad R.; Hall, Bryan D.; Innes, A. Micheil; Kalish, Jennifer M.; Keppler-Noreuil, Kim M.; Kosaki, Kenjiro; Kozel, Beth A.; Mirzaa, Ghayda M.; Mulvihill, John J.; Nowaczyk, Malgorzata J.M.; Pagon, Roberta A.; Retterer, Kyle; Rope, Alan F.; Sanchez-Lara, Pedro A.; Seaver, Laurie H.; Shieh, Joseph T.; Slavotinek, Anne M.; Sobering, Andrew K.; Stevens, Cathy A.; Stevenson, David A.; Tan, Tiong Yang; Tan, Wen-Hann; Tsai, Anne C.; Weaver, David D.; Williams, Marc S.; Zackai, Elaine; Zarate, Yuri A.; Medical and Molecular Genetics, School of Medicine