Divergent variant patterns among 19 patients with Rubinstein‐Taybi syndrome uncovered by comprehensive genetic analysis including whole genome sequencing. Issue 3 (4th January 2022)

• Record Type: Journal Article
• Authors: Enomoto, Yumi; Yokoi, Takayuki; Tsurusaki, Yoshinori; Murakami, Hiroaki; Tominaga, Makiko; Minatogawa, Mari; Abe‐Hatano, Chihiro; Kuroda, Yukiko; Ohashi, Ikuko; Ida, Kazumi; Shiiya, Shizuka; Kumaki, Tatsuro; Naruto, Takuya; Mitsui, Jun; Harada, Noriaki; Kido, Yasuhiro; Kurosawa, Kenji
• Is Part Of: Clinical genetics. Volume 101:Issue 3(2022)
• Page Start: 335
• Page End: 345
• Publication Date: 2022-01-04
• Subjects: abnormal development of the neural tube -- cloaca -- non‐coding regions -- Rubinstein‐Taybi syndrome -- whole genome sequencing; Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.14103
• Languages: English
• ISSNs: 0009-9163

Abstract

Abstract: Rubinstein‐Taybi syndrome (RSTS) is characterized by dysmorphic facial features, broad thumbs, and intellectual disability. CREB‐binding protein ( CREBBP ) or E1A‐binding protein P300 ( EP300 ) are causative genes. To elucidate the underlying genetic and genomic architecture related to the RSTS phenotype, we performed comprehensive genetic analysis targeting CREBBP and/or EP300 in 22 clinically diagnosed patients. During the 11‐year study period, we used several analysis methods including high‐resolution melting, array‐based comparative genomic hybridization, panel‐based exome sequencing, whole exome sequencing, and whole genome sequencing (WGS). We identified the causative variants in 19 patients (86.3%), but they were variable and complex, so we must combine multiple analysis methods. Notably, we found genetic alterations in the non‐coding regions of two patients (10.5%, 2/19): scattered deletions including a partial 5′‐untranslated region of CREBBP in one patient (all coding exons were intact), and a deep 229‐bp intronic deletion in another patient, resulting in a splicing error. Furthermore, we identified rare clinical findings: two patients with an EP300 variant showed abnormal development of the neural tube, and one patient with a CREBBP variant had anorectal atresia with a cloaca. Our findings expand the allelic heterogeneity of RSTS, underscore the utility of comprehensive genetic analysis, and suggest that WGS may be a practical diagnostic strategy. Abstract : Whole genome sequencing detected scattered deletions including a partial 5′‐untranslated region of CREB‐binding protein (all coding exons were intact).