RESUMO
BACKGROUND: Chromosomal microarray (CMA) testing is a first-tier test for patients with developmental delay, autism, or congenital anomalies. It increases diagnostic yield for patients with developmental delay or intellectual disability. In some countries, including Korea, CMA testing is not yet implemented in clinical practice. We assessed the diagnostic utility of CMA testing in a large cohort of patients with developmental delay or intellectual disability in Korea. METHODS: We conducted a genome-wide microarray analysis of 649 consecutive patients with developmental delay or intellectual disability at the Seoul National University Children's Hospital. Medical records were reviewed retrospectively. Pathogenicity of detected copy number variations (CNVs) was evaluated by referencing previous reports or parental testing using FISH or quantitative PCR. RESULTS: We found 110 patients to have pathogenic CNVs, which included 100 deletions and 31 duplications of 270 kb to 30 Mb. The diagnostic yield was 16.9%, demonstrating the diagnostic utility of CMA testing in clinic. Parental testing was performed in 66 patients, 86.4% of which carried de novo CNVs. In eight patients, pathogenic CNVs were inherited from healthy parents with a balanced translocation, and genetic counseling was provided to these families. We verified five rarely reported deletions on 2p21p16.3, 3p21.31, 10p11.22, 14q24.2, and 21q22.13. CONCLUSIONS: This study demonstrated the clinical utility of CMA testing in the genetic diagnosis of patients with developmental delay or intellectual disability. CMA testing should be included as a clinical diagnostic test for all children with developmental delay or intellectual disability.
Assuntos
Cromossomos/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiência Intelectual/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos/metabolismo , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Feminino , Duplicação Gênica , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Cariotipagem , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Deleção de Sequência , Adulto JovemRESUMO
The voltage-gated sodium channel genes and HOXD genes are clustered on chromosome 2q, and duplication of this region is associated with 2 clinical phenotypes: early-onset epilepsy and mesomelic dysplasia Kantaputra type, respectively. We report a case involving 2q24.3-2q32.1 duplication encompassing both the voltage-gated sodium channel and HOXD gene clusters, which were detected by a comparative genomic hybridization array. The associated clinical features were early-infantile-onset epilepsy, hypoplastic left heart syndrome, and global developmental delay. However, no features of mesomelic dysplasia were found. A fluorescent in situ hybridization study showed that the noncontiguous insertion of the duplicated chromosome 2q segment into chromosome 6q was inherited from the father, who has a balanced insertional translocation. The unique genotype-phenotype correlation in the present case suggests that dosage-sensitive effects might apply only to the voltage-gated sodium channel genes.
Assuntos
Síndrome de Aicardi/genética , Espasmos Infantis/genética , Trissomia/genética , Síndrome de Aicardi/fisiopatologia , Encéfalo/fisiopatologia , Cromossomos Humanos Par 2/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Eletroencefalografia , Pai , Humanos , Síndrome do Coração Esquerdo Hipoplásico/genética , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Hibridização in Situ Fluorescente , Lactente , Masculino , Fenótipo , Espasmos Infantis/fisiopatologia , Translocação Genética , Trissomia/fisiopatologiaRESUMO
We report a case of isodicentric chromosome 15 (idic(15) chromosome), the presence of which resulted in uncontrolled seizures, including epileptic spasms, tonic seizures, and global developmental delay. A 10-month-old female infant was referred to our pediatric neurology clinic because of uncontrolled seizures and global developmental delay. She had generalized tonic-clonic seizures since 7 months of age. At referral, she could not control her head and presented with generalized hypotonia. Her brain magnetic resonance imaging scans and metabolic evaluation results were normal. Routine karyotyping indicated the presence of a supernumerary marker chromosome of unknown origin (47, XX +mar). An array-comparative genomic hybridization (CGH) analysis revealed amplification from 15q11.1 to 15q13.1. Subsequent fluorescence in situ hybridization analysis confirmed a idic(15) chromosome. Array-CGH analysis has the advantage in determining the unknown origin of a supernumerary marker chromosome, and could be a useful method for the genetic diagnosis of epilepsy syndromes associated with various chromosomal aberrations.