Thomas Challman - Academia.edu (original) (raw)

Uploads

Papers by Thomas Challman

Research paper thumbnail of Additional file 1 of Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

Research paper thumbnail of Phenotypic and genotypic description of 44 patients with variants in DLG4 encoding the post-synaptic density protein PSD-95

European Journal of Human Genetics, Dec 1, 2020

Research paper thumbnail of The value of genomic variant ClinVar submissions from clinical providers: Beyond the addition of novel variants

Human Mutation, 2018

With the increasing use of clinical genomic testing across broad medical disciplines, the need fo... more With the increasing use of clinical genomic testing across broad medical disciplines, the need for data sharing and curation efforts to improve variant interpretation is paramount. The National Center for Biotechnology Information (NCBI) ClinVar database facilitates these efforts by serving as a repository for clinical assertions about genomic variants and associations with disease. Most variant submissions are from clinical laboratories, which may lack clinical details. Laboratories may also choose not to submit all variants. Clinical providers can contribute to variant interpretation improvements by submitting variants to ClinVar with their own assertions and supporting evidence. The medical genetics team at Geisinger's Autism & Developmental Medicine Institute routinely reviews the clinical significance of all variants obtained through clinical genomic testing, using published ACMG/AMP guidelines, clinical correlation, and post-test clinical data. We describe the submission of 148 sequence and 155 copy number variants to ClinVar as "provider interpretations." Of these, 192 (63.4%) were novel to ClinVar. Detailed clinical data were provided for 298 (98.3%), and when available, segregation data and follow-up clinical correlation or testing was included. This contribution marks the first large-scale submission from a neurodevelopmental clinical setting and illustrates the importance of clinical providers in collaborative efforts to improve variant interpretation.

Research paper thumbnail of Pain insensitivity: distal S6-segment mutations in NaV1.9 emerge as critical hotspot

Neurogenetics, Jan 13, 2017

Research paper thumbnail of The yield of the medical evaluation of children with pervasive developmental disorders

Journal of Autism and Developmental Disorders

Little information is available regarding the yield of the medical evaluation of children diagnos... more Little information is available regarding the yield of the medical evaluation of children diagnosed with pervasive developmental disorder-not otherwise specified (PDD-NOS) compared to children diagnosed with autistic disorder. Medical records were reviewed for 182 patients less than 18 years of age with either PDD-NOS or autistic disorder evaluated between 1994 and 1998 at Mayo Clinic. A condition likely to be etiologically relevant was identified in 6/117 (5.1%) patients diagnosed with PDD-NOS and 2/65 (3.1%) patients diagnosed with autistic disorder. Genetic disorders, both chromosomal and single-gene, were the most commonly identified conditions. Seizure disorders, electroencephalogram abnormalities, and anomalies on brain imaging were common in both groups. The likelihood of uncovering an etiologically relevant condition in children diagnosed with either PDD-NOS or autistic disorder may be equivalent. The scope of the etiological search in an individual patient with an autistic ...

Research paper thumbnail of Variable Phenotypic Expressivity of Specific Copy Number Variants and Single Gene Mutations in Autism and Other Neurodevelopmental Disorders

Background: Autism spectrum disorders (ASD), like intellectual disabilities, can be caused by man... more Background: Autism spectrum disorders (ASD), like intellectual disabilities, can be caused by many different highly penetrant genetic abnormalities, including mutations and genomic imbalances. These variants are individually rare but collectively common; even though no single genetic variant accounts for more than 1-1.5% of ASD, together they currently explain the etiology of approximately 15% of cases. However, it is also becoming apparent that identical variants may lead to ASD in some individuals and to other neurodevelopmental disorders in other individuals, including members of the same family. Objectives: The objective of this literature review was to examine the variable phenotypic expression of selected DNA copy number variants (CNVs) and single-gene variants that are known to cause autism spectrum disorders (ASD). Methods: In a case-control study involving 15,749 cases and 10,118 published controls, the International Standards for Cytogenomic Arrays (ISCA) consortium identi...

Research paper thumbnail of Methylphenidate: Its Pharmacology and Uses

Mayo Clinic Proceedings, 2000

Methylphenidate is a commonly used medication in the United States. This central nervous system s... more Methylphenidate is a commonly used medication in the United States. This central nervous system stimulant has a mechanism of action distinct from that of amphetamine. The Food and Drug Administration has approved methylphenidate for the treatment of attention-deficit/hyperactivity disorder and narcolepsy. Treatment with methylphenidate has been advocated in patients with traumatic brain injury and stroke, cancer patients, and those with human immunodeficiency virus infection. Placebo-controlled trials have documented its efficacyas an adjunctive M ethylphenidate (Ritalin) is a commonly used medication in the United States. First synthesized in 1944, methylphenidate was initially used as an analeptic for reversal of barbiturate-induced coma. I It is now primarily used as treatment of attention-deficit/hyperactivity disorder (ADHD). Estimates are that more than 2 million Americans, mostly children, are currently being treated with methylphenidate.' While concerns regarding overuse have been raised,' methylphenidate clearly has utility in several clinical situations. Recent articles have reviewed I or more aspects of methylphenidate use."'? The goals of this article are to provide a focused review for the clinician regarding what is known about the mechanism of action and pharmacology of methylphenidate and to appraise critically its therapeutic uses. Particular emphasis is given to newer uses in the adult population. CHEMISTRY AND MECHANISM OF ACTION Methylphenidate is a piperidine-derived central nervous system stimulant. The methylphenidate molecule possesses 2 centers of chirality; thus, a total of 4 enantiomers of this drug exist (Figure I). The earliest marketed preparations of methylphenidate contained all 4 enantiomers. Subsequent study revealed, however, that the erythro isomers were devoid of any major central nervous system stimulant effect." As a result, currently available prepara

Research paper thumbnail of Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

American Journal of Medical Genetics Part A, 2021

The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurod... more The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neur...

Research paper thumbnail of The Childhood Routines Inventory in Children with Autism Spectrum Disorders

Background: Until recently, the study of restricted, repetitive behavior (RRB) in autism spectrum... more Background: Until recently, the study of restricted, repetitive behavior (RRB) in autism spectrum disorders (ASD) has been largely neglected relative to the research on the language and social deficits associated with ASD. This may be due in part to the high prevalence of repetitive behavior that presents in other, non-ASD neurodevelopmental disorders, which might obscure the diagnostic utility of RRB. Objectives: We aim to examine the similarities and differences in RRB in children with ASD relative to a heterogeneous non-ASD sample, as well as to subgroups varying in ASD and cognitive status. First, we explore the factor structure of the Childhood Routines Inventory (CRI), a measure of RRB (Evans, Leckman, Carter, Reznick, Henshaw, King & Pauls, 1997) on a large sample of children with neurodevelopmental disorders, and then compare the CRI factors across various clinical subgroups. Methods: Over 1000 consecutive patients at a clinic for neurodevelopmental disorders in rural Centra...

Research paper thumbnail of End-stage renal failure in Smith–Magenis syndrome

American Journal of Medical Genetics Part A, 2007

Research paper thumbnail of Congenital heart defects associated with Smith-Magenis syndrome: Two cases of total anomalous pulmonary venous return

American Journal of Medical Genetics, 2004

Research paper thumbnail of Additional file 1 of Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

Research paper thumbnail of Phenotypic and genotypic description of 44 patients with variants in DLG4 encoding the post-synaptic density protein PSD-95

European Journal of Human Genetics, Dec 1, 2020

Research paper thumbnail of The value of genomic variant ClinVar submissions from clinical providers: Beyond the addition of novel variants

Human Mutation, 2018

With the increasing use of clinical genomic testing across broad medical disciplines, the need fo... more With the increasing use of clinical genomic testing across broad medical disciplines, the need for data sharing and curation efforts to improve variant interpretation is paramount. The National Center for Biotechnology Information (NCBI) ClinVar database facilitates these efforts by serving as a repository for clinical assertions about genomic variants and associations with disease. Most variant submissions are from clinical laboratories, which may lack clinical details. Laboratories may also choose not to submit all variants. Clinical providers can contribute to variant interpretation improvements by submitting variants to ClinVar with their own assertions and supporting evidence. The medical genetics team at Geisinger's Autism & Developmental Medicine Institute routinely reviews the clinical significance of all variants obtained through clinical genomic testing, using published ACMG/AMP guidelines, clinical correlation, and post-test clinical data. We describe the submission of 148 sequence and 155 copy number variants to ClinVar as "provider interpretations." Of these, 192 (63.4%) were novel to ClinVar. Detailed clinical data were provided for 298 (98.3%), and when available, segregation data and follow-up clinical correlation or testing was included. This contribution marks the first large-scale submission from a neurodevelopmental clinical setting and illustrates the importance of clinical providers in collaborative efforts to improve variant interpretation.

Research paper thumbnail of Pain insensitivity: distal S6-segment mutations in NaV1.9 emerge as critical hotspot

Neurogenetics, Jan 13, 2017

Research paper thumbnail of The yield of the medical evaluation of children with pervasive developmental disorders

Journal of Autism and Developmental Disorders

Little information is available regarding the yield of the medical evaluation of children diagnos... more Little information is available regarding the yield of the medical evaluation of children diagnosed with pervasive developmental disorder-not otherwise specified (PDD-NOS) compared to children diagnosed with autistic disorder. Medical records were reviewed for 182 patients less than 18 years of age with either PDD-NOS or autistic disorder evaluated between 1994 and 1998 at Mayo Clinic. A condition likely to be etiologically relevant was identified in 6/117 (5.1%) patients diagnosed with PDD-NOS and 2/65 (3.1%) patients diagnosed with autistic disorder. Genetic disorders, both chromosomal and single-gene, were the most commonly identified conditions. Seizure disorders, electroencephalogram abnormalities, and anomalies on brain imaging were common in both groups. The likelihood of uncovering an etiologically relevant condition in children diagnosed with either PDD-NOS or autistic disorder may be equivalent. The scope of the etiological search in an individual patient with an autistic ...

Research paper thumbnail of Variable Phenotypic Expressivity of Specific Copy Number Variants and Single Gene Mutations in Autism and Other Neurodevelopmental Disorders

Background: Autism spectrum disorders (ASD), like intellectual disabilities, can be caused by man... more Background: Autism spectrum disorders (ASD), like intellectual disabilities, can be caused by many different highly penetrant genetic abnormalities, including mutations and genomic imbalances. These variants are individually rare but collectively common; even though no single genetic variant accounts for more than 1-1.5% of ASD, together they currently explain the etiology of approximately 15% of cases. However, it is also becoming apparent that identical variants may lead to ASD in some individuals and to other neurodevelopmental disorders in other individuals, including members of the same family. Objectives: The objective of this literature review was to examine the variable phenotypic expression of selected DNA copy number variants (CNVs) and single-gene variants that are known to cause autism spectrum disorders (ASD). Methods: In a case-control study involving 15,749 cases and 10,118 published controls, the International Standards for Cytogenomic Arrays (ISCA) consortium identi...

Research paper thumbnail of Methylphenidate: Its Pharmacology and Uses

Mayo Clinic Proceedings, 2000

Methylphenidate is a commonly used medication in the United States. This central nervous system s... more Methylphenidate is a commonly used medication in the United States. This central nervous system stimulant has a mechanism of action distinct from that of amphetamine. The Food and Drug Administration has approved methylphenidate for the treatment of attention-deficit/hyperactivity disorder and narcolepsy. Treatment with methylphenidate has been advocated in patients with traumatic brain injury and stroke, cancer patients, and those with human immunodeficiency virus infection. Placebo-controlled trials have documented its efficacyas an adjunctive M ethylphenidate (Ritalin) is a commonly used medication in the United States. First synthesized in 1944, methylphenidate was initially used as an analeptic for reversal of barbiturate-induced coma. I It is now primarily used as treatment of attention-deficit/hyperactivity disorder (ADHD). Estimates are that more than 2 million Americans, mostly children, are currently being treated with methylphenidate.' While concerns regarding overuse have been raised,' methylphenidate clearly has utility in several clinical situations. Recent articles have reviewed I or more aspects of methylphenidate use."'? The goals of this article are to provide a focused review for the clinician regarding what is known about the mechanism of action and pharmacology of methylphenidate and to appraise critically its therapeutic uses. Particular emphasis is given to newer uses in the adult population. CHEMISTRY AND MECHANISM OF ACTION Methylphenidate is a piperidine-derived central nervous system stimulant. The methylphenidate molecule possesses 2 centers of chirality; thus, a total of 4 enantiomers of this drug exist (Figure I). The earliest marketed preparations of methylphenidate contained all 4 enantiomers. Subsequent study revealed, however, that the erythro isomers were devoid of any major central nervous system stimulant effect." As a result, currently available prepara

Research paper thumbnail of Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

American Journal of Medical Genetics Part A, 2021

The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurod... more The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neur...

Research paper thumbnail of The Childhood Routines Inventory in Children with Autism Spectrum Disorders

Background: Until recently, the study of restricted, repetitive behavior (RRB) in autism spectrum... more Background: Until recently, the study of restricted, repetitive behavior (RRB) in autism spectrum disorders (ASD) has been largely neglected relative to the research on the language and social deficits associated with ASD. This may be due in part to the high prevalence of repetitive behavior that presents in other, non-ASD neurodevelopmental disorders, which might obscure the diagnostic utility of RRB. Objectives: We aim to examine the similarities and differences in RRB in children with ASD relative to a heterogeneous non-ASD sample, as well as to subgroups varying in ASD and cognitive status. First, we explore the factor structure of the Childhood Routines Inventory (CRI), a measure of RRB (Evans, Leckman, Carter, Reznick, Henshaw, King & Pauls, 1997) on a large sample of children with neurodevelopmental disorders, and then compare the CRI factors across various clinical subgroups. Methods: Over 1000 consecutive patients at a clinic for neurodevelopmental disorders in rural Centra...

Research paper thumbnail of End-stage renal failure in Smith–Magenis syndrome

American Journal of Medical Genetics Part A, 2007

Research paper thumbnail of Congenital heart defects associated with Smith-Magenis syndrome: Two cases of total anomalous pulmonary venous return

American Journal of Medical Genetics, 2004