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Paul Grossfeld - One of the best experts on this subject based on the ideXlab platform.
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partial Jacobsen Syndrome phenotype in a patient with a de novo frameshift mutation in the ets1 transcription factor
Cold Spring Harb Mol Case Stud, 2019Co-Authors: Eva Tootleman, Barbara Malamut, Natacha Akshoomoff, Sarah N Mattson, Hal M Hoffman, Marilyn C Jones, Beth F Printz, Sergey A Shiryaev, Paul GrossfeldAbstract:Jacobsen Syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen Syndrome phenotype. One gene, ETS1, has been implicated in causing congenital heart defects, structural kidney defects, and immunodeficiency. We performed a comprehensive phenotypic analysis on a patient with congenital heart disease previously found to have a de novo frameshift mutation in ETS1, resulting in the loss of the DNA-binding domain of the protein. Our results suggest that loss of Ets1 causes a "partial Jacobsen Syndrome phenotype" including congenital heart disease, facial dysmorphism, intellectual disability, and attention deficit hyperactivity disorder.
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Successful Management of a Patient With Jacobsen Syndrome and Hypoplastic Left Heart Syndrome
World journal for pediatric & congenital heart surgery, 2019Co-Authors: Nicole L. Herrick, John J. Lamberti, Paul Grossfeld, Raghav MurthyAbstract:Jacobsen Syndrome (JS) is a rare genetic condition characterized by intellectual disability, hematologic abnormalities, and congenital heart defects. A male infant presented at birth with phenotypi...
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gene targeted deletion in mice of the ets 1 transcription factor a candidate gene in the Jacobsen Syndrome kidney critical region causes abnormal kidney development
American Journal of Medical Genetics Part A, 2019Co-Authors: Dongrui Chen, Teresa Mattina, Orsetta Zufardi, Elena Rossi, Kevin T Bush, Sanjay K Nigam, Paul GrossfeldAbstract:Ets-1 is a member of the Ets family of transcription factors and has critical roles in multiple biological functions. Structural kidney defects occur at an increased frequency in Jacobsen Syndrome (OMIM #147791), a rare chromosomal disorder caused by deletions in distal 11q, implicating at least one causal gene in distal 11q. In this study, we define an 8.1 Mb "critical region" for kidney defects in Jacobsen Syndrome, which spans ~50 genes. We demonstrate that gene-targeted deletion of Ets-1 in mice results in some of the most common congenital kidney defects occurring in Jacobsen Syndrome, including: duplicated kidney, hypoplastic kidney, and dilated renal pelvis and calyces. Taken together, our results implicate Ets-1 in normal mammalian kidney development and, potentially, in the pathogenesis of some of the most common types of human structural kidney defects.
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Brain hemorrhages in Jacobsen Syndrome: A retrospective review of six cases and clinical recommendations
American Journal of Medical Genetics Part A, 2017Co-Authors: Paul GrossfeldAbstract:Jacobsen Syndrome is a rare chromosomal disorder caused by distal deletions in the long arm of chromosome 11. All patients with Jacobsen Syndrome have Paris–Trousseau Syndrome, a bleeding disorder that causes neonatal thrombocytopenia, and persistent platelet dysfunction. Despite that, to date there are no reported cases of hemorrhagic strokes occurring in patients with Jacobsen Syndrome. In the last 6 years at least six cases of brain hemorrhages in patients with Jacobsen Syndrome have occurred. In this report, we perform a retrospective review of these six cases. The analysis indicates that the etiology of brain hemorrhages in Jacobsen Syndrome is likely multifactorial. A likely cause (or causes) was identified in three of the cases, and additional potential risk factors were identified. Based on these findings, clinical recommendations are provided that should aid in the identification of those individuals with Jacobsen Syndrome that are at increased risk for brain hemorrhages, and will hopefully decrease the occurrence of this devastating complication in people with Jacobsen Syndrome.© 2017 Wiley Periodicals, Inc.
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px rics deficient mice mimic autism spectrum disorder in Jacobsen Syndrome through impaired gabaa receptor trafficking
Nature Communications, 2016Co-Authors: Tsutomu Nakamura, Paul Grossfeld, Natacha Akshoomoff, Sarah N Mattson, Fumiko Arimayoshida, Fumika Sakaue, Yukiko Nasunishimura, Yasuko Takeda, Ken Matsuura, Toshiya ManabeAbstract:Jacobsen Syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.
Leopold M G Curfs - One of the best experts on this subject based on the ideXlab platform.
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exploration of differences in types of sleep disturbance and severity of sleep problems between individuals with cri du chat Syndrome down s Syndrome and Jacobsen Syndrome a case control study
Research in Developmental Disabilities, 2012Co-Authors: A P H M Maas, Robert Didden, H P L M Korzilius, Leopold M G CurfsAbstract:The prevalence of sleep problems in individuals with intellectual disability (ID) seems to vary between genetic Syndromes associated with ID. Different types of sleep disturbances may indicate underlying causes of sleep problems and these types of sleep disturbances may vary between different genetic Syndromes. We examined and compared five types of sleep disturbance as well as severity of sleep problems in individuals with Cri du Chat Syndrome (CDC), Down's Syndrome (DS), Jacobsen Syndrome (JS), and individuals with non-specific ID (NS). We used Simonds and Parraga's Sleep Questionnaire (1982) to assess prevalence of types of sleep disturbance and to explore differences in types of sleep disturbance and severity of sleep problems between the four diagnostic groups. In each group, mean scores for Snoring were significantly higher than those for Sleep apnea and Snoring was the most prevalent type of sleep disturbance in CDC, DS, and JS. The mean score on Complaints related to sleep was remarkably high in the JS group. There were no differences in severity of sleep problems between groups. These findings suggest that snoring is an important underlying cause of sleep problems in individuals with CDS, DS, and JS.
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sleep problems in individuals with 11q terminal deletion disorder Jacobsen Syndrome
Genetic Counseling, 2008Co-Authors: A P H M Maas, Paul Grossfeld, Robert Didden, H P L M Korzilius, W J Braam, Marcel G Smits, Leopold M G CurfsAbstract:Summary: Sleep problems in individuals with 11q terminal deletion disorder (Jacobsen Syndrome): Characteristics of sleep and sleep problems were investigated in 43 individuals with 11q terminal deletion disorder (Jacobsen Syndrome). Data were collected using a sleep questionnaire. Ten individuals (23%) had a sleep problem. Settling problems, frequent night waking and early waking occurred in 2 (4%), 7 (16%) and 2 (6%) individuals, respectively. Twenty-two individuals (54%) had a history of sleep problems. Twenty-five individuals (60%) showed restless sleep and 23 individuals (54%) slept in an unusual position. Apart from frequent coughs, no significant relationships were found between the presence of a sleep problem and other variables, such as age, level of ID, breathing problems, heart defects, constipation, daytime activity and behavioral diagnosis, restless sleep and sleeping in an unusual positions. Key-words: 11q terminal deletion disorder - Jacobsen Syndrome - Sleep problems - Sleep questionnaire. INTRODUCTION 11q terminal deletion disorder (Jacobsen Syndrome) is a rare genetic disorder, caused by a terminal deletion in the long arm of chromosome 11. It is characterized by psychomotor retardation, congenital heart defects, blood dyscrasias (Paris-Trousseau Syndrome) and craniofacial anomalies. Seizures are uncommon in this Syndrome. Cognitive level in individuals with Jacobsen Syndrome usually ranges from near normal intelligence to moderate intellectual disability (see e.g. Grossfeld et al. (6)). Sleep problems may be part of genetic Syndromes associated with intellectual disability. Compared to matched controls, prevalence of specific sleep problems has been found to be higher among individuals with a genetic disorder than in those without a disorder. A relatively high prevalence of sleep problems were found in Down, fragile-X, Smith-Magenis, Prader-Willi, Angelman and Rett Syndrome (e.g. 2-4, 7, 9-11). Little is known about the characteristics of sleep or the frequency of sleep problems in Jacobsen Syndrome. Our knowledge on sleep problems in individuals with Jacobsen Syndrome is primarily based on anecdotal information and clinical experience, suggesting that sleep problems in individuals with Jacobsen Syndrome may be prevalent. Furthermore, it is not known what other neurocognitive and/or medical problems may be associated with sleep problems in these patients. To date, no study has been performed that characterizes sleep and sleep problems in individuals with Jacobsen Syndrome, and factors that may be related to sleep problems in this group. Therefore, in the present study, (a) characteristics of sleep and sleep problems were investigated in a relatively large sample (N = 43) of individuals with Jacobsen Syndrome, (b) parental management with their child's sleep problem was investigated, and (c) relationships between the presence of a sleep problem and other variables (e.g., age, level of intellectual disability and medical problems) were explored. METHOD PARTICIPANTS AND PROCEDURE A standardized sleep questionnaire (see Sleep Questionnaire) was sent to parents who were members of the American 11q Research and Resource Group. Only individuals with a terminal deletion at chromosome 11q (Jacobsen Syndrome) and who were living at home with their parents were included. Parents were asked to complete the Sleep Questionnaire. MATERIALS Sleep Questionnaire The Sleep Questionnaire was adapted from Wiggs and Stores (14), Didden, Korzilius, Van Aperlo, Van Overloop and De Vries (5) and Didden et al. (4) and consisted of five parts. Part one addresses demographic information (e.g., presence of seizure disorder and heart defect). The second part covers current (i.e. last three months) behaviors related to settling to sleep, night waking and early waking. Questions about frequency of occurrence (e.g., "How often does your child wake in the night? …
Natacha Akshoomoff - One of the best experts on this subject based on the ideXlab platform.
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partial Jacobsen Syndrome phenotype in a patient with a de novo frameshift mutation in the ets1 transcription factor
Cold Spring Harb Mol Case Stud, 2019Co-Authors: Eva Tootleman, Barbara Malamut, Natacha Akshoomoff, Sarah N Mattson, Hal M Hoffman, Marilyn C Jones, Beth F Printz, Sergey A Shiryaev, Paul GrossfeldAbstract:Jacobsen Syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen Syndrome phenotype. One gene, ETS1, has been implicated in causing congenital heart defects, structural kidney defects, and immunodeficiency. We performed a comprehensive phenotypic analysis on a patient with congenital heart disease previously found to have a de novo frameshift mutation in ETS1, resulting in the loss of the DNA-binding domain of the protein. Our results suggest that loss of Ets1 causes a "partial Jacobsen Syndrome phenotype" including congenital heart disease, facial dysmorphism, intellectual disability, and attention deficit hyperactivity disorder.
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px rics deficient mice mimic autism spectrum disorder in Jacobsen Syndrome through impaired gabaa receptor trafficking
Nature Communications, 2016Co-Authors: Tsutomu Nakamura, Paul Grossfeld, Natacha Akshoomoff, Sarah N Mattson, Fumiko Arimayoshida, Fumika Sakaue, Yukiko Nasunishimura, Yasuko Takeda, Ken Matsuura, Toshiya ManabeAbstract:Jacobsen Syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.
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Jacobsen Syndrome: Advances in our knowledge of phenotype and genotype
American journal of medical genetics. Part C Seminars in medical genetics, 2015Co-Authors: Rémi Favier, Sarah N Mattson, Natacha Akshoomoff, Paul GrossfeldAbstract:In 1973, the Danish geneticist Petrea Jacobsen described a three-generation family in which the proband carried a presumed terminal deletion at the end of the long arm of chromosome 11 (11q). This patient had dysmorphic features, congenital heart disease, and intellectual disability. Since Dr. Jacobsen's initial report, over 200 patients with Jacobsen Syndrome have been reported, suggesting that Jacobsen Syndrome is a contiguous gene disorder. With the advent of high resolution deletion mapping and the completion of the human genome sequencing project, a comprehensive genotype/phenotype analysis for Jacobsen Syndrome became possible. In this article, we review research describing individual causal genes in distal 11q that contribute to the overall Jacobsen Syndrome clinical phenotype. Through a combination of human genetics and the use of genetically engineered animal models, causal genes have been identified for the clinical problems in JS that historically have caused the greatest morbidity and mortality: congenital heart disease, the Paris-Trousseau bleeding disorder, intellectual disability, autism, and immunodeficiency. Insights gained from these studies are being applied for future drug development and clinical trials, as well as for a potential strategy for the prevention of certain forms of congenital heart disease. The results of these studies will likely not only improve the prognostic and therapeutic approaches for patients with Jacobsen Syndrome, but also for the general population afflicted with these problems.
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evidence for autism spectrum disorder in Jacobsen Syndrome identification of a candidate gene in distal 11q
Genetics in Medicine, 2015Co-Authors: Natacha Akshoomoff, Sarah N Mattson, Paul GrossfeldAbstract:Evidence for autism spectrum disorder in Jacobsen Syndrome: identification of a candidate gene in distal 11q
James G White - One of the best experts on this subject based on the ideXlab platform.
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platelet storage pool deficiency in Jacobsen Syndrome
Platelets, 2007Co-Authors: James G WhiteAbstract:Jacobsen Syndrome and Paris-Trousseau Syndrome share similar congenital anomalies, thrombocytopenia, giant platelet alpha granules resulting from fusion of smaller organelles, and an 11q terminal deletion at 11q23.3. Similarities in the two cohorts have suggested that the Paris-Trousseau Syndrome is a variant of Jacobsen Syndrome, or the same disorder. The present study has pointed out a significant difference between the two Syndromes. Platelets from six patients with Jacobsen Syndrome were markedly diminished in serotonin adenine nucleotide rich dense bodies, indicating the presence of platelet storage pool deficiency. Since platelet dense bodies are reported to be normal in size, number and distribution in the Paris-Trousseau Syndrome, the presence of platelet storage pool deficiency in six patients evaluated in the present study may distinguish the two disorders.
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paris trousseau Syndrome platelets in a child with Jacobsen s Syndrome
American Journal of Hematology, 2001Co-Authors: L Krishnamurti, Joseph P Neglia, Rajaram Nagarajan, Susan A Berry, Jamie L Lohr, Betsy A Hirsch, James G WhiteAbstract:The thrombocytopenia in an infant with clinical features of Jacobsen's Syndrome characterized by multiple congenital anomalies, cardiac defects, psychomotor retardation, and deletion of chromosome 11 at 11q23.3 has been evaluated. Study of his platelets in the electron microscope revealed giant alpha granules in his cells identical in appearance to those reported in the family with Paris-Trousseau Syndrome. As a result, the Paris-Trousseau Syndrome appears to be a variant of the Jacobsen Syndrome, and the thrombocytopenia observed in all cases of chromosome 11q23.3 deletion due to dysmegakaryopoieses. Giant alpha granules are frequently observed in normal platelets during long-term storage and may form in Jacobsen and Paris-Trousseau platelets during prolonged residence in the bone marrow.
Sarah N Mattson - One of the best experts on this subject based on the ideXlab platform.
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partial Jacobsen Syndrome phenotype in a patient with a de novo frameshift mutation in the ets1 transcription factor
Cold Spring Harb Mol Case Stud, 2019Co-Authors: Eva Tootleman, Barbara Malamut, Natacha Akshoomoff, Sarah N Mattson, Hal M Hoffman, Marilyn C Jones, Beth F Printz, Sergey A Shiryaev, Paul GrossfeldAbstract:Jacobsen Syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen Syndrome phenotype. One gene, ETS1, has been implicated in causing congenital heart defects, structural kidney defects, and immunodeficiency. We performed a comprehensive phenotypic analysis on a patient with congenital heart disease previously found to have a de novo frameshift mutation in ETS1, resulting in the loss of the DNA-binding domain of the protein. Our results suggest that loss of Ets1 causes a "partial Jacobsen Syndrome phenotype" including congenital heart disease, facial dysmorphism, intellectual disability, and attention deficit hyperactivity disorder.
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px rics deficient mice mimic autism spectrum disorder in Jacobsen Syndrome through impaired gabaa receptor trafficking
Nature Communications, 2016Co-Authors: Tsutomu Nakamura, Paul Grossfeld, Natacha Akshoomoff, Sarah N Mattson, Fumiko Arimayoshida, Fumika Sakaue, Yukiko Nasunishimura, Yasuko Takeda, Ken Matsuura, Toshiya ManabeAbstract:Jacobsen Syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.
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Jacobsen Syndrome: Advances in our knowledge of phenotype and genotype
American journal of medical genetics. Part C Seminars in medical genetics, 2015Co-Authors: Rémi Favier, Sarah N Mattson, Natacha Akshoomoff, Paul GrossfeldAbstract:In 1973, the Danish geneticist Petrea Jacobsen described a three-generation family in which the proband carried a presumed terminal deletion at the end of the long arm of chromosome 11 (11q). This patient had dysmorphic features, congenital heart disease, and intellectual disability. Since Dr. Jacobsen's initial report, over 200 patients with Jacobsen Syndrome have been reported, suggesting that Jacobsen Syndrome is a contiguous gene disorder. With the advent of high resolution deletion mapping and the completion of the human genome sequencing project, a comprehensive genotype/phenotype analysis for Jacobsen Syndrome became possible. In this article, we review research describing individual causal genes in distal 11q that contribute to the overall Jacobsen Syndrome clinical phenotype. Through a combination of human genetics and the use of genetically engineered animal models, causal genes have been identified for the clinical problems in JS that historically have caused the greatest morbidity and mortality: congenital heart disease, the Paris-Trousseau bleeding disorder, intellectual disability, autism, and immunodeficiency. Insights gained from these studies are being applied for future drug development and clinical trials, as well as for a potential strategy for the prevention of certain forms of congenital heart disease. The results of these studies will likely not only improve the prognostic and therapeutic approaches for patients with Jacobsen Syndrome, but also for the general population afflicted with these problems.
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evidence for autism spectrum disorder in Jacobsen Syndrome identification of a candidate gene in distal 11q
Genetics in Medicine, 2015Co-Authors: Natacha Akshoomoff, Sarah N Mattson, Paul GrossfeldAbstract:Evidence for autism spectrum disorder in Jacobsen Syndrome: identification of a candidate gene in distal 11q
