Divergent variant patterns among 19 patients withRubinstein‐Taybisyndrome uncovered by comprehensive genetic analysis including whole genome sequencing

Abstract

Rubinstein-Taybi syndrome (RSTS) is characterized by dysmorphic facial features, broad thumbs, and intellectual disability. CREB-binding protein (CREBBP) or E1Abinding 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 0 -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. K E Y W O R D S abnormal development of the neural tube, cloaca, non-coding regions, Rubinstein-Taybi syndrome, whole genome sequencing 1 | INTRODUCTION Rubinstein-Taybi syndrome (RSTS) is a multiple malformation disorder characterized by dysmorphic facial features, broad thumbs and first toes, short stature, and moderate to severe intellectual disability.Common facial features of RSTS include downward slanting palpebral fissures, arcuate eyebrows, convex nasal ridge, high-arched palate, talon cusp, and grimacing smile. 1,2 RSTS is a rare autosomal dominant

Correlations between phenotype and gene region-specific episignatures in Rubinstein-Taybi syndrome and Menke-Hennekam syndrome

“…To comprehensively evaluate phenotype similarities and differences, we further collected clinical information from our patients and literatures published previously (3,(7)(8)(9)(10)(11)(12)(13)(14)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). In total, 37 MKHK and 151 RSTS patients (including 115 classical RSTS and 36 patients with non-NMD variants) were enrolled (Table 2).…”

Complex congenital cardiovascular anomaly in a patient with AGO1‐associated disorder

“…Sequencing data were analyzed with the Burrows‐Wheeler Alignment SAMTools, Picard, the Genome Analysis Toolkit, and ANNOVAR or SnpEff for variant annotation. Copy number variation analysis was performed using the log2‐ratio of read depth on each exon as described previously (Enomoto et al, 2022). We identified a novel variant, NM_012199.5:c.1891C > T:p.(Arg631*), in AGO1 (Figure 2).…”

“…Copy number variation analysis was performed using the log2-ratio of read depth on each exon as described previously (Enomoto et al, 2022). We identified a novel variant, NM_012199.5: c.1891C > T:p.(Arg631*), in AGO1 (Figure 2).…”