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Session


Keywords: Dysmorphology; Characterization of syndromes; Genetic testing; Mendelian disorder; Natural history

Authors:
R. Kosaki 1; H. Okuno 2; K. Kosaki 3

Affiliations:
1) Div Med Genet, Natl Ctr Child Hlth & Dev, Tokyo, Japan; 2) Department of Physiology, Keio University School of Medicine; 3) Center for Medical Genetics, Keio University School of Medicine


?Background?Rubinstein-Taybi syndrome(RSTS) is a multiple malformation syndrome characterized by typical facial appearance, broad thumbs and toes, and developmental delay. RSTS is an extremely rare autosomal dominant genetic disease. An estimated prevalence of one case per 125,000 live births.
The diagnosis of RSTS is primarily based on clinical features with distinctive facial features and hand and foot abnormalities. RSTS is caused by heterozygous mutations in CREBBP and in EP300 genes in fifty to sixty percent and eight to ten percent. EP300 is responsible for a minority case of RSTS, the phenotype has been shown various spectrum. Some do not have characteristic facies nor hand and foot abnormalities. Intellectual disability also appears to be affected mildly.
?Purpose?
The purpose is to describe three unrelated RSTS patients without classic manifestations who have EP300 mutations.
?Method?
We examined three intellectual disability /developmental delay with congenital multiple malformations.
Genomic DNA was extracted from a peripheral blood sample. Medical exome sequencing was performed using the TruSight One Sequencing Panel (Illumina San Diego, CA) running on a MiSeq platform (Illumina, San Diego, CA). The bioinformatics analysis was performed. The mutation was confirmed using Sanger sequencing.
?Result?
Case1: A 5-months old boy with developmental delay, large VSD and broad thumbs.We identified with EP300 nonsense mutation.
Case2: A 2-years old girl with intellectual disability, downslanting palpebral fissures, and slightly big toes. We identified with EP300 missense mutation.
Case3: A 11-months old girl with DORV, TR, myelomeningocele, hydrocephalus, imperforate anus, coloboma and hearing impairment. We identified de novoEP300 frameshift mutation and de novo SOS1 mutation.
Case4:A 6-years old girl with PDA,PS,coloboma and hearing impairment.We identified de novoEP300 frameshift mutation.
?Discussion?
We showed the clinical variability of RSTS with EP300 mutations which provided the expansion of RSTS spectrum. It will contribute the genotype-phenotype correlation in RSTS. We also showed the clinical utility of medical exome analysis as a diagnostic test in patients with congenital multiple malformations.

Informed consent from the parents and approval from the local institutional review board were obtained prior to the molecular studies.
There are no conflicts of interest to declare.