RESUMO
OBJECTIVES: To ascertain a molecular genetic diagnosis for subjects with neonatal/infantile intrahepatic cholestasis (NIIC) by the use of next-generation sequencing (NGS) and to perform a genotype-phenotype correlation. STUDY DESIGN: We recruited Japanese subjects with NIIC who had no definitive molecular genetic diagnosis. We developed a diagnostic custom panel of 18 genes, and the amplicon library was sequenced via NGS. We then compared clinical data between the molecular genetically confirmed subjects with NIIC. RESULTS: We analyzed 109 patients with NIIC ("genetic cholestasis," 31 subjects; "unknown with complications" such as prematurity, 46 subjects; "unknown without complications," 32 subjects), and a molecular genetic diagnosis was made for 28 subjects (26%). The rate of positive molecular genetic diagnosis in each category was 22 of 31 (71%) for the "genetic cholestasis" group, 2 of 46 (4.3%) for the "unknown with complications" group, and 4 of 32 (12.5%) for the "unknown without complications" group. The grouping of the molecular diagnoses in the group with genetic cholestasis was as follows: 12 with Alagille syndrome, 5 with neonatal Dubin-Johnson syndrome, 5 with neonatal intrahepatic cholestasis caused by citrin deficiency, and 6 with progressive familial intrahepatic cholestasis or benign recurrent intrahepatic cholestasis with low gamma-glutamyl transpeptidase levels. Several clinical datasets, including age of onset, direct bilirubin, and aminotransferases, were significantly different between the disorders confirmed using molecular genetic diagnosis. CONCLUSION: Targeted NGS can be used for molecular genetic diagnosis in subjects with NIIC. Clinical diagnosis should be accordingly redefined in the view of molecular genetic findings.
Assuntos
Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/genética , Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Bilirrubina/sangue , Proteínas de Ligação ao Cálcio/deficiência , Aberrações Cromossômicas , Éxons , Feminino , Deleção de Genes , Estudos de Associação Genética , Genômica , Humanos , Lactente , Recém-Nascido , Japão , Icterícia Idiopática Crônica/diagnóstico , Icterícia Idiopática Crônica/genética , Masculino , Biologia Molecular , Transportadores de Ânions Orgânicos/deficiência , gama-Glutamiltransferase/genéticaRESUMO
In neonatal-onset nonketotic hyperglycinemia, severe psychomotor retardation is the expected uniform outcome. We report two patients with typical neonatal presentation who showed far better developmental outcomes. The in vitro expression analysis of the identified GLDC mutations revealed considerable residual enzyme activity, suggesting prognostic and enzymatic heterogeneity even in neonatal-onset nonketotic hyperglycinemia.