Rubinstein-Taybi 2 associated to novel EP300 mutations: deepening the clinical and genetic spectrum
Por:
López M, García-Oguiza A, Armstrong-Moron J, García-Cobaleda I, García-Miñaur S, Santos-Simarro F, Seidel V and Domínguez-Garrido E
Publicada:
5 mar 2018
Ahead of Print:
5 mar 2018
Resumen:
Background: Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder characterized by broad thumbs and halluces. RSTS is caused by mutations in CREBBP and in EP300 genes in 50-60% and 8%, respectively. Up to now, 76 RSTS-EP300 patients have been described. We present the clinical and molecular characterization of a cohort of RSTS patients carrying EP300 mutations.
Methods: Patients were selected from a cohort of 72 individuals suspected of RSTS after being negative in CREBBP study. MLPA and panel-based NGS EP300 were performed.
Results: Eight patients were found to carry EP300 mutations. Phenotypic characteristics included: intellectual disability (generally mild), postnatal growth retardation, infant feeding problems, psychomotor and language delay and typical facial dysmorphisms (microcephaly, downslanting palpebral fissures, columella below the alae nasi, and prominent nose). Broad thumbs and/or halluces were common, but angulated thumbs were only found in two patients. We identified across the gene novel mutations, including large deletion, frameshift mutations, nonsense, missense and splicing alterations, confirming de novo origin in all but one (the mother, possibly underdiagnosed, has short and broad thumbs and had learning difficulties).
Conclusions: The clinical evaluation of our patients corroborates that clinical features in EP300 are less marked than in CREBBP patients although it is difficult to establish a genotype-phenotype correlation although. It is remarkable that these findings are observed in a RSTS-diagnosed cohort; some patients harbouring EP300 mutations could present a different phenotype. Broadening the knowledge about EP300-RSTS phenotype may contribute to improve the management of patients and the counselling to the families.
Filiaciones:
López M:
Molecular Diagnostic Unit, Fundación Rioja Salud, Logroño, La Rioja, Spain
García-Oguiza A:
Department of Pediatrics, San Pedro Hospital, Logroño, Spain
Armstrong-Moron J:
Servei de Medicina Genètica i Molecular, Institut de Recerca Pediàtrica and Department of Neurology Hospital Sant Joan de Déu (HSJD), CIBERER, Catalonia, Spain
García-Cobaleda I:
Unidad de Fertilidad y Diagnóstico Genético, Hospital Univ. Ntra. Sra. de La Candelaria, Santa Cruz de Tenerife, Spain
García-Miñaur S:
Sección de Genética Clínica, INGEMM (Instituto de Genética Médica y Molecular), U753, CIBERER, Madrid, Spain
Santos-Simarro F:
Sección de Genética Clínica, INGEMM (Instituto de Genética Médica y Molecular), U753, CIBERER, Madrid, Spain
Seidel V:
Clinical Genetics, Department of Pediatrics, Hospital General Universitario Gregorio Marañón, Madrid, Spain
Domínguez-Garrido E:
Molecular Diagnostic Unit, Fundación Rioja Salud, Logroño, La Rioja, Spain.
Green Submitted, gold
|