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Hum Mutat ; 39(11): 1660-1667, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311381


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.

Genoma Humano/genética , Transtorno do Espectro Autista , Bases de Dados Genéticas , Testes Genéticos , Variação Genética/genética , Genômica , Humanos
JAMA Psychiatry ; 72(2): 119-26, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25493922


IMPORTANCE: Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood. OBJECTIVES: To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs. DESIGN, SETTING, AND PARTICIPANTS: Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project. MAIN OUTCOMES AND MEASURES: We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison. RESULTS: A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD for neuromotor performance (P < .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07). CONCLUSIONS AND RELEVANCE: Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their children's developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders.

Transtorno Autístico/fisiopatologia , Transtornos Cromossômicos/fisiopatologia , Deficiência Intelectual/fisiopatologia , Inteligência/genética , Pais , Fenótipo , Desempenho Psicomotor/fisiologia , Comportamento Social , Adulto , Transtorno Autístico/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Irmãos
Lancet Neurol ; 12(4): 406-14, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23518333


Neurodevelopmental disorders can be caused by many different genetic abnormalities that are individually rare but collectively common. Specific genetic causes, including certain copy number variants and single-gene mutations, are shared among disorders that are thought to be clinically distinct. This evidence of variability in the clinical manifestations of individual genetic variants and sharing of genetic causes among clinically distinct brain disorders is consistent with the concept of developmental brain dysfunction, a term we use to describe the abnormal brain function underlying a group of neurodevelopmental and neuropsychiatric disorders and to encompass a subset of various clinical diagnoses. Although many pathogenic genetic variants are currently thought to be variably penetrant, we hypothesise that when disorders encompassed by developmental brain dysfunction are considered as a group, the penetrance will approach 100%. The penetrance is also predicted to approach 100% when the phenotype being considered is a specific trait, such as intelligence or autistic-like social impairment, and the trait could be assessed using a continuous, quantitative measure to compare probands with non-carrier family members rather than a qualitative, dichotomous trait and comparing probands with the healthy population.

Encefalopatias/diagnóstico , Encefalopatias/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Animais , Transtorno Autístico/diagnóstico , Transtorno Autístico/epidemiologia , Transtorno Autístico/genética , Encefalopatias/epidemiologia , Deficiências do Desenvolvimento/epidemiologia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/genética
J Autism Dev Disord ; 33(2): 187-92, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12757358


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 spectrum disorder should not be limited by the specific diagnostic category.

Transtorno Autístico/etiologia , Transtornos Globais do Desenvolvimento Infantil/etiologia , Equipe de Assistência ao Paciente , Adolescente , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Transtorno Autístico/psicologia , Dano Encefálico Crônico/complicações , Dano Encefálico Crônico/diagnóstico , Dano Encefálico Crônico/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/psicologia , Pré-Escolar , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Diagnóstico Diferencial , Feminino , Aconselhamento Genético , Humanos , Lactente , Masculino , Prognóstico , Fatores de Risco