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Michael Shevell - One of the best experts on this subject based on the ideXlab platform.
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genetics and the investigation of Developmental Delay intellectual disability
Archives of Disease in Childhood, 2014Co-Authors: Myriam Srour, Michael ShevellAbstract:Global Developmental Delay and intellectual disabilities are common reasons for diagnostic assessment by paediatricians. There are a multiplicity of possible causes many of which have genetic, management and treatment implications for the child and family. Genetic causes are estimated to be responsible for approximately a quarter to one-half of identified cases. The multiplicity of individually rare genetic causes challenges the practitioner with respect to the selection of diagnostic tests and accurate diagnosis. To assist the practitioner practice guidelines have been formulated and these are reviewed and summarised in this particular article.
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child health and parental stress in school age children with a preschool diagnosis of Developmental Delay
Journal of Child Neurology, 2008Co-Authors: Richard Webster, Robert W. Platt, Annette Majnemer, Michael ShevellAbstract:Chronic disorders are known to have a wide-ranging impact on overall health and family dynamics. The objective of this study was to assess child health and well-being and parental stress in a cohort of school-age children diagnosed before school entry with either global Developmental Delay or Developmental language impairment. In total, 65 children with preschool Developmental Delay were assessed at school age (mean ± SD age: 7.3 ± 0.7 years) with the Child Health Questionnaire and Parenting Stress Index, with a mean interval between assessment of 3.9 years. Almost all children who completed testing (60/62) continued to show Developmental impairments across domains. On the Child Health Questionnaire, children showed the greatest impairment on the mental health scale (median z score: —0.9). The median Child Health Questionnaire psychosocial health score (40.7) was almost 1 SD below established normative values ( P < .001). More than 40% of parents had a Parenting Stress Index above the 85th percentile (cli...
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child health and parental stress in school age children with a preschool diagnosis of Developmental Delay
Journal of Child Neurology, 2008Co-Authors: Richard Webster, Robert W. Platt, Annette Majnemer, Michael ShevellAbstract:Chronic disorders are known to have a wide-ranging impact on overall health and family dynamics. The objective of this study was to assess child health and well-being and parental stress in a cohort of school-age children diagnosed before school entry with either global Developmental Delay or Developmental language impairment. In total, 65 children with preschool Developmental Delay were assessed at school age (mean +/- SD age: 7.3 +/- 0.7 years) with the Child Health Questionnaire and Parenting Stress Index, with a mean interval between assessment of 3.9 years. Almost all children who completed testing (60/62) continued to show Developmental impairments across domains. On the Child Health Questionnaire, children showed the greatest impairment on the mental health scale (median z score: -0.9). The median Child Health Questionnaire psychosocial health score (40.7) was almost 1 SD below established normative values ( P < .001). More than 40% of parents had a Parenting Stress Index above the 85th percentile (clinically significant parenting stress). Using multiple linear regression analysis, high levels of parenting stress were best predicted by a child's Child Health Questionnaire psychosocial health score (r2 = 0.49, P < .001). Thus, 4 years after a preschool-age diagnosis of Developmental Delay, poor psychosocial health was a common comorbidity. Almost half the parents showed clinically significant levels of parenting stress. There is a need to both recognize and provide ongoing social and emotional support for young children diagnosed with Developmental disability and their families.
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analysis of clinical features predicting etiologic yield in the assessment of global Developmental Delay
Pediatrics, 2006Co-Authors: Myriam Srour, Barbara Mazer, Michael ShevellAbstract:OBJECTIVE. Global Developmental Delay is a common reason for presentation for neurologic evaluation. This study examined the role of clinical features in predicting the identification of an underlying cause for a child9s global Developmental Delay. METHODS. Over a 10-year inclusive interval, the case records of all consecutive children RESULTS. A total of 261 patients eventually met criteria for study inclusion. Mean age at initial evaluation was 33.6 months. An underlying cause was found in 98 children. Commonest etiologic groupings were genetic syndrome/chromosomal abnormality, intrapartum asphyxia, cerebral dysgenesis, psychosocial deprivation, and toxin exposure. Factors associated with the ability to eventually identify an underlying cause included female gender (40 of 68 vs 58 of 193), abnormal prenatal/perinatal history (52 of 85 vs 46 of 176), absence of autistic features (85 of 159 vs 13 of 102), presence of microcephaly (26 of 40 vs 72 of 221), abnormal neurologic examination (52 of 71 vs 46 of 190), and dysmorphic features (44 of 84 vs 54 of 177). In 113 children without any abnormal features identified on history or physical examination, routine screening investigations (karyotype, fragile X molecular genotyping, and neuroimaging) revealed an underlying etiology in 18. CONCLUSIONS. Etiologic yield in an unselected series of young children with global Developmental Delay is close to 40% overall and 55% in the absence of any coexisting autistic features. Clinical features are readily apparent that may enhance an expectation of a successful etiologic search. Screening investigations may yield an underlying cause.
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Diagnosing Sotos syndrome in the setting of global Developmental Delay and macrocephaly.
Journal of Child Neurology, 2006Co-Authors: Myriam Srour, Barbara Mazer, Michael ShevellAbstract:Sotos syndrome (cerebral gigantism) is characterized by macrocephaly, global Developmental Delay, characteristic facial dysmorphology, and a markedly advanced bone age. The purpose of this study was to describe the prevalence of Sotos syndrome in a consecutive series of patients with global Developmental Delay, which might modify our laboratory evaluation approach to this particular clinical situation. For a 10-year inclusive interval, the case records of all consecutive patients referred for global Developmental Delay in a single pediatric neurology practice were reviewed. Patients with macrocephaly were defined by an age- and gender-adjusted head circumference greater than or equal to the 98th percentile. Possible clinical factors associated with eventual diagnosis of Sotos syndrome in this group of macrocephalic children were tested with a two-tailed Fisher exact test. Of 261 children with global Developmental Delay, 18 (7%) had documented macrocephaly. Of these 18 children, 3 (17%) had an advanced bone age and were diagnosed with Sotos syndrome. In patients with global Developmental Delay and concomitant macrocephaly, Sotos syndrome is not uncommon. Assessment of bone age is a simple screening test for diagnosis of this entity and should be undertaken routinely in children with macrocephaly and global Developmental Delay even in the absence of other distinctive syndromic clinical features.
Carl Baker - One of the best experts on this subject based on the ideXlab platform.
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refining analyses of copy number variation identifies specific genes associated with Developmental Delay
Nature Genetics, 2014Co-Authors: Bradley P. Coe, Carl Baker, Jill A Rosenfeld, Kali Witherspoon, Bregje W M Van Bon, Anneke Vultovan T Silfhout, Paolo Bosco, Kathryn Friend, Serafino BuonoAbstract:Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with Developmental Delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with Developmental Delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.
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a copy number variation morbidity map of Developmental Delay
Nature Genetics, 2011Co-Authors: Gregory M Cooper, Tiffany H. Vu, Santhosh Girirajan, Rizwan Hamid, Carl Baker, Jill A Rosenfeld, Charles A Williams, Heather J Stalker, Vickie L Hannig, Hoda AbdelhamidAbstract:Evan Eichler and colleagues analyze copy number variation in 15,767 children with intellectual disability, Developmental Delay, congenital birth defects and/or other related phenotypes. They identify 59 likely pathogenic CNV regions, including 14 new candidate regions, and estimate that ~14% of disorders in this sample collection are caused by large CNVs.
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A copy number variation morbidity map of Developmental Delay
Nature Genetics, 2011Co-Authors: Gregory M Cooper, Bradley P. Coe, Tiffany H. Vu, Heather Stalker, Santhosh Girirajan, Charles Williams, Rizwan Hamid, Carl Baker, Jill A Rosenfeld, Vickie HannigAbstract:To understand the genetic heterogeneity underlying Developmental Delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of Developmental Delay, intellectual disability and autism spectrum disorders.
Jill A Rosenfeld - One of the best experts on this subject based on the ideXlab platform.
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refining analyses of copy number variation identifies specific genes associated with Developmental Delay
Nature Genetics, 2014Co-Authors: Bradley P. Coe, Carl Baker, Jill A Rosenfeld, Kali Witherspoon, Bregje W M Van Bon, Anneke Vultovan T Silfhout, Paolo Bosco, Kathryn Friend, Serafino BuonoAbstract:Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with Developmental Delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with Developmental Delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.
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a copy number variation morbidity map of Developmental Delay
Nature Genetics, 2011Co-Authors: Gregory M Cooper, Tiffany H. Vu, Santhosh Girirajan, Rizwan Hamid, Carl Baker, Jill A Rosenfeld, Charles A Williams, Heather J Stalker, Vickie L Hannig, Hoda AbdelhamidAbstract:Evan Eichler and colleagues analyze copy number variation in 15,767 children with intellectual disability, Developmental Delay, congenital birth defects and/or other related phenotypes. They identify 59 likely pathogenic CNV regions, including 14 new candidate regions, and estimate that ~14% of disorders in this sample collection are caused by large CNVs.
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A copy number variation morbidity map of Developmental Delay
Nature Genetics, 2011Co-Authors: Gregory M Cooper, Bradley P. Coe, Tiffany H. Vu, Heather Stalker, Santhosh Girirajan, Charles Williams, Rizwan Hamid, Carl Baker, Jill A Rosenfeld, Vickie HannigAbstract:To understand the genetic heterogeneity underlying Developmental Delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of Developmental Delay, intellectual disability and autism spectrum disorders.
Gregory M Cooper - One of the best experts on this subject based on the ideXlab platform.
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a copy number variation morbidity map of Developmental Delay
Nature Genetics, 2011Co-Authors: Gregory M Cooper, Tiffany H. Vu, Santhosh Girirajan, Rizwan Hamid, Carl Baker, Jill A Rosenfeld, Charles A Williams, Heather J Stalker, Vickie L Hannig, Hoda AbdelhamidAbstract:Evan Eichler and colleagues analyze copy number variation in 15,767 children with intellectual disability, Developmental Delay, congenital birth defects and/or other related phenotypes. They identify 59 likely pathogenic CNV regions, including 14 new candidate regions, and estimate that ~14% of disorders in this sample collection are caused by large CNVs.
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A copy number variation morbidity map of Developmental Delay
Nature Genetics, 2011Co-Authors: Gregory M Cooper, Bradley P. Coe, Tiffany H. Vu, Heather Stalker, Santhosh Girirajan, Charles Williams, Rizwan Hamid, Carl Baker, Jill A Rosenfeld, Vickie HannigAbstract:To understand the genetic heterogeneity underlying Developmental Delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of Developmental Delay, intellectual disability and autism spectrum disorders.
S L Lee - One of the best experts on this subject based on the ideXlab platform.
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identification of mutations in the pi3k akt mtor signalling pathway in patients with macrocephaly and Developmental Delay and or autism
Molecular Autism, 2017Co-Authors: K S Yeung, Winnie W Y Tso, Christopher C Y Mak, Gordon K C Leung, Mandy H Y Tsang, Dingge Ying, Steven L C Pei, S L LeeAbstract:Macrocephaly, which is defined as a head circumference greater than or equal to + 2 standard deviations, is a feature commonly observed in children with Developmental Delay and/or autism spectrum disorder. Although PTEN is a well-known gene identified in patients with this syndromic presentation, other genes in the PI3K-AKT-mTOR signalling pathway have also recently been suggested to have important roles. The aim of this study is to characterise the mutation spectrum of this group of patients. We performed whole-exome sequencing of 21 patients with macrocephaly and Developmental Delay/autism spectrum disorder. Sources of genomic DNA included blood, buccal mucosa and saliva. Germline mutations were validated by Sanger sequencing, whereas somatic mutations were validated by droplet digital PCR. We identified ten pathogenic/likely pathogenic mutations in PTEN (n = 4), PIK3CA (n = 3), MTOR (n = 1) and PPP2R5D (n = 2) in ten patients. An additional PTEN mutation, which was classified as variant of unknown significance, was identified in a patient with a pathogenic PTEN mutation, making him harbour bi-allelic germline PTEN mutations. Two patients harboured somatic PIK3CA mutations, and the level of somatic mosaicism in blood DNA was low. Patients who tested positive for mutations in the PI3K-AKT-mTOR pathway had a lower Developmental quotient than the rest of the cohort (DQ = 62.8 vs. 76.1, p = 0.021). Their dysmorphic features were non-specific, except for macrocephaly. Among the ten patients with identified mutations, brain magnetic resonance imaging was performed in nine, all of whom showed megalencephaly. We identified mutations in the PI3K-AKT-mTOR signalling pathway in nearly half of our patients with macrocephaly and Developmental Delay/autism spectrum disorder. These patients have subtle dysmorphic features and mild Developmental issues. Clinically, patients with germline mutations are difficult to distinguish from patients with somatic mutations, and therefore, sequencing of buccal or saliva DNA is important to identify somatic mosaicism. Given the high diagnostic yield and the management implications, we suggest implementing comprehensive genetic testing in the PI3K-AKT-mTOR pathway in the clinical evaluation of patients with macrocephaly and Developmental Delay and/or autism spectrum disorder.
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Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and Developmental Delay and/or autism
BMC, 2017Co-Authors: K S Yeung, Winnie W Y Tso, Christopher C Y Mak, Gordon K C Leung, Mandy H Y Tsang, Dingge Ying, Steven L C Pei, S L Lee, Wanling YangAbstract:Abstract Background Macrocephaly, which is defined as a head circumference greater than or equal to + 2 standard deviations, is a feature commonly observed in children with Developmental Delay and/or autism spectrum disorder. Although PTEN is a well-known gene identified in patients with this syndromic presentation, other genes in the PI3K-AKT-mTOR signalling pathway have also recently been suggested to have important roles. The aim of this study is to characterise the mutation spectrum of this group of patients. Methods We performed whole-exome sequencing of 21 patients with macrocephaly and Developmental Delay/autism spectrum disorder. Sources of genomic DNA included blood, buccal mucosa and saliva. Germline mutations were validated by Sanger sequencing, whereas somatic mutations were validated by droplet digital PCR. Results We identified ten pathogenic/likely pathogenic mutations in PTEN (n = 4), PIK3CA (n = 3), MTOR (n = 1) and PPP2R5D (n = 2) in ten patients. An additional PTEN mutation, which was classified as variant of unknown significance, was identified in a patient with a pathogenic PTEN mutation, making him harbour bi-allelic germline PTEN mutations. Two patients harboured somatic PIK3CA mutations, and the level of somatic mosaicism in blood DNA was low. Patients who tested positive for mutations in the PI3K-AKT-mTOR pathway had a lower Developmental quotient than the rest of the cohort (DQ = 62.8 vs. 76.1, p = 0.021). Their dysmorphic features were non-specific, except for macrocephaly. Among the ten patients with identified mutations, brain magnetic resonance imaging was performed in nine, all of whom showed megalencephaly. Conclusion We identified mutations in the PI3K-AKT-mTOR signalling pathway in nearly half of our patients with macrocephaly and Developmental Delay/autism spectrum disorder. These patients have subtle dysmorphic features and mild Developmental issues. Clinically, patients with germline mutations are difficult to distinguish from patients with somatic mutations, and therefore, sequencing of buccal or saliva DNA is important to identify somatic mosaicism. Given the high diagnostic yield and the management implications, we suggest implementing comprehensive genetic testing in the PI3K-AKT-mTOR pathway in the clinical evaluation of patients with macrocephaly and Developmental Delay and/or autism spectrum disorder
