The Experts below are selected from a list of 12558 Experts worldwide ranked by ideXlab platform
Sylvie Roux - One of the best experts on this subject based on the ideXlab platform.
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autism is a Prenatal Disorder evidence from late gestation brain overgrowth
Autism Research, 2018Co-Authors: Frederique Bonnetbrilhault, Toky A Rajerison, Christian Paillet, Marie Guimardbrunault, Agathe Saby, Laura Ponson, Gabriele Tripi, Joelle Malvy, Sylvie RouxAbstract:This retrospective study aimed to specify the critical period for atypical brain development in individuals with autism spectrum Disorder (ASD) using Prenatal and postnatal head growth parameters. The sample consisted of 80 Caucasian, unrelated, idiopathic patients with ASD born after 1995. Fetal ultrasound parameters (head circumference [HC], abdominal circumference, and femur length) were obtained during the second and third trimesters of gestation. HC at birth and postnatal parameters at 12 and 24 months of age were also collected. Head overgrowth, assessed by HC, was highlighted during the second (20-26 weeks of amenorrhea) and third (28-36 weeks of amenorrhea) trimesters. Normal growth of body fetal parameters indicated that head overgrowth was not because of overall body overgrowth. Moreover, postnatal results replicated previously and reported head overgrowth. A critical time window for atypical brain development in autism is hypothesized to begin from the 22nd week of amenorrhea. This period is critical for cortical lamination and glial activation. A pathophysiological cascade is suggested with interactions between candidate genes and environmental factors. Autism Research 2018, 11: 1635-1642. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It is now widely acknowledged in the scientific community, that autism is a neurodevelopmental Disorder. Recent evidence from animal and pathological studies has implicated the in utero period. However, the precise time of onset of abnormal brain development remains unknown. This retrospective study reports novel findings, identifying an atypical head growth trajectory in children with autism, during the in utero period (after the 22nd week of amenorrhea). In the same children, postnatal head overgrowth was also observed. Late gestation is identified as a critical period for atypical brain development underlying autism symptoms.
Frederique Bonnetbrilhault - One of the best experts on this subject based on the ideXlab platform.
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autism is a Prenatal Disorder evidence from late gestation brain overgrowth
Autism Research, 2018Co-Authors: Frederique Bonnetbrilhault, Toky A Rajerison, Christian Paillet, Marie Guimardbrunault, Agathe Saby, Laura Ponson, Gabriele Tripi, Joelle Malvy, Sylvie RouxAbstract:This retrospective study aimed to specify the critical period for atypical brain development in individuals with autism spectrum Disorder (ASD) using Prenatal and postnatal head growth parameters. The sample consisted of 80 Caucasian, unrelated, idiopathic patients with ASD born after 1995. Fetal ultrasound parameters (head circumference [HC], abdominal circumference, and femur length) were obtained during the second and third trimesters of gestation. HC at birth and postnatal parameters at 12 and 24 months of age were also collected. Head overgrowth, assessed by HC, was highlighted during the second (20-26 weeks of amenorrhea) and third (28-36 weeks of amenorrhea) trimesters. Normal growth of body fetal parameters indicated that head overgrowth was not because of overall body overgrowth. Moreover, postnatal results replicated previously and reported head overgrowth. A critical time window for atypical brain development in autism is hypothesized to begin from the 22nd week of amenorrhea. This period is critical for cortical lamination and glial activation. A pathophysiological cascade is suggested with interactions between candidate genes and environmental factors. Autism Research 2018, 11: 1635-1642. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It is now widely acknowledged in the scientific community, that autism is a neurodevelopmental Disorder. Recent evidence from animal and pathological studies has implicated the in utero period. However, the precise time of onset of abnormal brain development remains unknown. This retrospective study reports novel findings, identifying an atypical head growth trajectory in children with autism, during the in utero period (after the 22nd week of amenorrhea). In the same children, postnatal head overgrowth was also observed. Late gestation is identified as a critical period for atypical brain development underlying autism symptoms.
Brady Paul - One of the best experts on this subject based on the ideXlab platform.
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Prenatale Chromosomale Microarray Analyse en Identificatie van Genetische Variaties bij Congenitale Hernia Diafragmatica.
2014Co-Authors: Brady PaulAbstract:Chromosomal microarray analysis has gradually replaced conventional karyotyping over recent years in the postnatal setting which has revolutionized whole genome screening for genomic imbalances in patients. We sought to evaluate the benefits and the challenges of applying chromosomal microarrays to Prenatal diagnosis for referrals with abnormal ultrasound findings. Our findings, presented in Chapter 3, demonstrate a diagnostic yield of ~10%. Importantly, ~3% are caused by submicroscopic CNVs which would go undetected by conventional karyotyping alone. Furthermore, the higher resolution offered by chromosomal microarray analysis led to important additional information in ~4% of patients. Of particular interest we discover a novel and unexpected advantage of arrays; a 500kb paternal insertional translocation is the likely driver of a de novo unbalanced translocation, thus improving recurrence risk calculation in this family. Our study has, in part, paved the way for the recent Summary Guidelines for Prenatal Chromosomal Microarray Analysis and Genetic Counselling from the Belgian Society for Human Genetics [http://www.beshg.be/download/annex_2_summary_of_array_and_Prenatal_guidelines_20130502.pdf]. The implementation of Prenatal chromosomal microarray analysis as the first tier test in place of conventional karyotyping brings the standard of Prenatal diagnosis in line with that which is provided for postnatal genetic diagnosis.Congenital diaphragmatic hernia (CDH) is a life-threatening Prenatal Disorder detectable by ultrasound during pregnancy. We sought to further unravel the genetic factors underlying isolated CDH by the design of a custom microarray covering genomic loci recurrently associated with CDH and candidate CDH genes. Our retrospective screen of 79 isolated CDH patients using this custom microarray is presented in Chapter 4. This study identified a novel duplication of the EFNB1 gene in a male patient which was considered likely to be pathogenic. Since our publication, a second case of a male CDH patient with duplication of EFNB1 was reported, thus reinforcing EFNB1 dosage sensitivity as a cause of isolated CDH. In order to further identify (novel) CNVs and genes associated with isolated CDH, we undertook a prospective Prenatal study using chromosomal microarrays with genome-wide coverage in 75 foetuses with isolated CDH, which is presented in Chapter 4. This study revealed submicroscopic de novo pathogenic CNVs in 9.3% and rare inherited variants which may be involved in CDH in a further 4% of foetuses. This diagnostic yield is significantly higher than the ~3% rate of pathogenic submicroscopic CNVs which we observed in our Prenatal study using the same microarray platform. Isolated CDH thus represents a valid cohort for CNV screening in the Prenatal phase, and suggests that the clinical utility of conventional karyotyping is questionable for this group of patients. This study allowed us to further refine the critical region at 15q26 to only 2 genes, pinpointing NR2F2 as the causal gene. We add further evidence for the 15q25.2 and 16p11.2 recurrent microdeletions as CDH loci, and we identify novel CNVs not previously observed in association with CDH, including a duplication of 4p15.2-p14.We next evaluated the use of exome sequencing for the investigation of isolated CDH and non-isolated CDH where a genetic cause was suspected. Our results show that exome sequencing represents an effective technique with which to investigate familial CDH, described in Chapter 5. In the first family studied, we identified a nonsense mutation in ZFPM2 in 2 individuals with isolated CDH, as well as a sibling with a congenital heart defect. Surprisingly, the mutation was shown to be transmitted from the unaffected mother, and is also carried by the maternal grandfather and the maternal sister, both of whom are also asymptomatic. This intriguing finding highlights the complexity of CDH, reinforcing the involvement of additional as yet unidentified (epi)genetic factors in CDH penetrance. In a second family with 2 male foetuses with MCA, we identify a mutation in the X-linked PORCN gene inherited from an unaffected mother who was shown to have extreme skewing of X-inactivation. This further implicates Wnt signaling as playing a role in CDH, as well as multiple aspects of foetal development. In a third consanguineous family we identify a mutation in PIGN in a foetus with MCA, inherited from carrier parents. PIGN is involved in GPI anchor synthesis and our finding adds to a growing body of evidence that defective GPI anchor synthesis causes multiple phenotypes in humans.Given the variation in severity of herniation and thus pulmonary hypoplasia, as well as differences in responses to foetal and / or neonatal therapy for CDH patients, we sought to explore whether gene expression analysis of amniotic fluid cells from CDH foetuses could identify dysregulated genes and biological pathways which may act as predictive biomarkers. In this exploratory study we applied RNA-sequencing to investigate gene expression in cultured cells sourced from amniotic fluid of isolated CDH patients, described in Chapter 6. This analysis identifies 2 potential molecular subtypes of isolated CDH, one of which is characterized by downregulation of TGFB1 and CTGF, and upregulation of TNF, IL6 and IL8. This highlights downregulation of TGFB signalling as a likely cause of much of of the downstream dysregulation in gene expression observed, including that of CTGF which has been previously implicated in the nitrofen rodent model of CDH. Furthermore, this group of patients shows an apparent inflammatory response indicated by the upregulation of TNF, IL6 and IL8 which may in turn exacerbate postnatal pulmonary hypertension. These findings direct future targeted studies in a larger cohort of isolated CDH patients to determine the clinical significance and therapeutic potential.status: publishe
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Prenatal Chromosomal Microarray Analysis and Identification of Genetic Variants in Congenital Diaphragmatic Hernia.
2014Co-Authors: Brady PaulAbstract:Chromosomal microarray analysis has gradually replaced conventional karyotyping over recent years in the postnatal setting which has revolutionized whole genome screening for genomic imbalances in patients. We sought to evaluate the benefits and the challenges of applying chromosomal microarrays to Prenatal diagnosis for referrals with abnormal ultrasound findings. Our findings, presented in Chapter 3, demonstrate a diagnostic yield of ~10%. Importantly, ~3% are caused by submicroscopic CNVs which would go undetected by conventional karyotyping alone. Furthermore, the higher resolution offered by chromosomal microarray analysis led to important additional information in ~4% of patients. Of particular interest we discover a novel and unexpected advantage of arrays; a 500kb paternal insertional translocation is the likely driver of a de novo unbalanced translocation, thus improving recurrence risk calculation in this family. Our study has, in part, paved the way for the recent Summary Guidelines for Prenatal Chromosomal Microarray Analysis and Genetic Counselling from the Belgian Society for Human Genetics [http://www.beshg.be/download/annex_2_summary_of_array_and_Prenatal_guidelines_20130502.pdf]. The implementation of Prenatal chromosomal microarray analysis as the first tier test in place of conventional karyotyping brings the standard of Prenatal diagnosis in line with that which is provided for postnatal genetic diagnosis.Congenital diaphragmatic hernia (CDH) is a life-threatening Prenatal Disorder detectable by ultrasound during pregnancy. We sought to further unravel the genetic factors underlying isolated CDH by the design of a custom microarray covering genomic loci recurrently associated with CDH and candidate CDH genes. Our retrospective screen of 79 isolated CDH patients using this custom microarray is presented in Chapter 4. This study identified a novel duplication of the EFNB1 gene in a male patient which was considered likely to be pathogenic. Since our publication, a second case of a male CDH patient with duplication of EFNB1 was reported, thus reinforcing EFNB1 dosage sensitivity as a cause of isolated CDH. In order to further identify (novel) CNVs and genes associated with isolated CDH, we undertook a prospective Prenatal study using chromosomal microarrays with genome-wide coverage in 75 foetuses with isolated CDH, which is presented in Chapter 4. This study revealed submicroscopic de novo pathogenic CNVs in 9.3% and rare inherited variants which may be involved in CDH in a further 4% of foetuses. This diagnostic yield is significantly higher than the ~3% rate of pathogenic submicroscopic CNVs which we observed in our Prenatal study using the same microarray platform. Isolated CDH thus represents a valid cohort for CNV screening in the Prenatal phase, and suggests that the clinical utility of conventional karyotyping is questionable for this group of patients. This study allowed us to further refine the critical region at 15q26 to only 2 genes, pinpointing NR2F2 as the causal gene. We add further evidence for the 15q25.2 and 16p11.2 recurrent microdeletions as CDH loci, and we identify novel CNVs not previously observed in association with CDH, including a duplication of 4p15.2-p14.We next evaluated the use of exome sequencing for the investigation of isolated CDH and non-isolated CDH where a genetic cause was suspected. Our results show that exome sequencing represents an effective technique with which to investigate familial CDH, described in Chapter 5. In the first family studied, we identified a nonsense mutation in ZFPM2 in 2 individuals with isolated CDH, as well as a sibling with a congenital heart defect. Surprisingly, the mutation was shown to be transmitted from the unaffected mother, and is also carried by the maternal grandfather and the maternal sister, both of whom are also asymptomatic. This intriguing finding highlights the complexity of CDH, reinforcing the involvement of additional as yet unidentified (epi)genetic factors in CDH penetrance. In a second family with 2 male foetuses with MCA, we identify a mutation in the X-linked PORCN gene inherited from an unaffected mother who was shown to have extreme skewing of X-inactivation. This further implicates Wnt signaling as playing a role in CDH, as well as multiple aspects of foetal development. In a third consanguineous family we identify a mutation in PIGN in a foetus with MCA, inherited from carrier parents. PIGN is involved in GPI anchor synthesis and our finding adds to a growing body of evidence that defective GPI anchor synthesis causes multiple phenotypes in humans.Given the variation in severity of herniation and thus pulmonary hypoplasia, as well as differences in responses to foetal and / or neonatal therapy for CDH patients, we sought to explore whether gene expression analysis of amniotic fluid cells from CDH foetuses could identify dysregulated genes and biological pathways which may act as predictive biomarkers. In this exploratory study we applied RNA-sequencing to investigate gene expression in cultured cells sourced from amniotic fluid of isolated CDH patients, described in Chapter 6. This analysis identifies 2 potential molecular subtypes of isolated CDH, one of which is characterized by downregulation of TGFB1 and CTGF, and upregulation of TNF, IL6 and IL8. This highlights downregulation of TGFB signalling as a likely cause of much of of the downstream dysregulation in gene expression observed, including that of CTGF which has been previously implicated in the nitrofen rodent model of CDH. Furthermore, this group of patients shows an apparent inflammatory response indicated by the upregulation of TNF, IL6 and IL8 which may in turn exacerbate postnatal pulmonary hypertension. These findings direct future targeted studies in a larger cohort of isolated CDH patients to determine the clinical significance and therapeutic potential.status: publishe
Toky A Rajerison - One of the best experts on this subject based on the ideXlab platform.
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autism is a Prenatal Disorder evidence from late gestation brain overgrowth
Autism Research, 2018Co-Authors: Frederique Bonnetbrilhault, Toky A Rajerison, Christian Paillet, Marie Guimardbrunault, Agathe Saby, Laura Ponson, Gabriele Tripi, Joelle Malvy, Sylvie RouxAbstract:This retrospective study aimed to specify the critical period for atypical brain development in individuals with autism spectrum Disorder (ASD) using Prenatal and postnatal head growth parameters. The sample consisted of 80 Caucasian, unrelated, idiopathic patients with ASD born after 1995. Fetal ultrasound parameters (head circumference [HC], abdominal circumference, and femur length) were obtained during the second and third trimesters of gestation. HC at birth and postnatal parameters at 12 and 24 months of age were also collected. Head overgrowth, assessed by HC, was highlighted during the second (20-26 weeks of amenorrhea) and third (28-36 weeks of amenorrhea) trimesters. Normal growth of body fetal parameters indicated that head overgrowth was not because of overall body overgrowth. Moreover, postnatal results replicated previously and reported head overgrowth. A critical time window for atypical brain development in autism is hypothesized to begin from the 22nd week of amenorrhea. This period is critical for cortical lamination and glial activation. A pathophysiological cascade is suggested with interactions between candidate genes and environmental factors. Autism Research 2018, 11: 1635-1642. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It is now widely acknowledged in the scientific community, that autism is a neurodevelopmental Disorder. Recent evidence from animal and pathological studies has implicated the in utero period. However, the precise time of onset of abnormal brain development remains unknown. This retrospective study reports novel findings, identifying an atypical head growth trajectory in children with autism, during the in utero period (after the 22nd week of amenorrhea). In the same children, postnatal head overgrowth was also observed. Late gestation is identified as a critical period for atypical brain development underlying autism symptoms.
Christian Paillet - One of the best experts on this subject based on the ideXlab platform.
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autism is a Prenatal Disorder evidence from late gestation brain overgrowth
Autism Research, 2018Co-Authors: Frederique Bonnetbrilhault, Toky A Rajerison, Christian Paillet, Marie Guimardbrunault, Agathe Saby, Laura Ponson, Gabriele Tripi, Joelle Malvy, Sylvie RouxAbstract:This retrospective study aimed to specify the critical period for atypical brain development in individuals with autism spectrum Disorder (ASD) using Prenatal and postnatal head growth parameters. The sample consisted of 80 Caucasian, unrelated, idiopathic patients with ASD born after 1995. Fetal ultrasound parameters (head circumference [HC], abdominal circumference, and femur length) were obtained during the second and third trimesters of gestation. HC at birth and postnatal parameters at 12 and 24 months of age were also collected. Head overgrowth, assessed by HC, was highlighted during the second (20-26 weeks of amenorrhea) and third (28-36 weeks of amenorrhea) trimesters. Normal growth of body fetal parameters indicated that head overgrowth was not because of overall body overgrowth. Moreover, postnatal results replicated previously and reported head overgrowth. A critical time window for atypical brain development in autism is hypothesized to begin from the 22nd week of amenorrhea. This period is critical for cortical lamination and glial activation. A pathophysiological cascade is suggested with interactions between candidate genes and environmental factors. Autism Research 2018, 11: 1635-1642. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It is now widely acknowledged in the scientific community, that autism is a neurodevelopmental Disorder. Recent evidence from animal and pathological studies has implicated the in utero period. However, the precise time of onset of abnormal brain development remains unknown. This retrospective study reports novel findings, identifying an atypical head growth trajectory in children with autism, during the in utero period (after the 22nd week of amenorrhea). In the same children, postnatal head overgrowth was also observed. Late gestation is identified as a critical period for atypical brain development underlying autism symptoms.