Case Report: Low-Level Maternal Mosaicism of a Novel CREBBP Variant Causes Recurrent Rubinstein-Taybi Syndrome in Two Siblings of a Chinese Family.

Shaobin Lin,Ting Lei,Yi Zhou,Jianzhu Wu,Jialiu Liu,Peizhi Huang,Linhuan Huang,Yanmin Luo,Zhiming He

doi:10.3389/fgene.2021.640992

Abstract

Familial Rubinstein-Taybi syndrome (RSTS) with recurrent RSTS siblings and apparently unaffected parents is rare; such cases might result from parental somatic and/or germline mosaicism. Parental low-level (<10%) germline mosaicism in the CREBBP-associated RSTS family has not been reported. Here, we present our studies of a Chinese family with two RSTS siblings and apparently unaffected parents. We detected the apparent de novo variant (DNV) c.3235C>T (p.Gln1079*) in CREBBP in the siblings via trio whole-exome sequencing. High-depth next-generation sequencing (NGS) for the parents revealed a low-level (<10%) mosaic variant in both the peripheral blood (3.64%) and buccal mucosa (1.94%) of the unaffected mother, indicating maternal somatic and germline mosaicism. Peripheral blood RNA-sequencing analysis for the patients and normal individuals indicated that the c.3235C>T (p.Gln1079*) non-sense variant did not trigger nonsense-mediated mRNA decay to reduce CREBBP mRNA levels. Transcriptome analysis revealed 151 downregulated mRNAs and 132 upregulated mRNAs between the patients and normal individuals. This study emphasizes that high-depth NGS using multiple specimens might be applied for a family with an affected sibling caused by an apparent CREBBP DNV to identify potential low-level parental mosaicism and provide an assessment of recurrence risk.

Highlights

Rubinstein-Taybi syndrome (RSTS) is a rare genetic syndrome featuring distinctive facial dysmorphisms, characteristic hand and foot findings, short stature, developmental delay, and intellectual disability, with a reported incidence of 1:100,000–1:125,000 births in the Netherlands (Hennekam et al, 1990; Wiley et al, 2003; Hennekam, 2006)
Familial CREBBP-associated RSTS in a parent-to-child transmission manner or a recurrent condition with multiple affected siblings and apparently unaffected parents in a family might result from parental somatic and/or germline mosaicism
CREBBP mosaic variants have been previously reported in eight RSTS cases (Table 2) (Gervasini et al, 2007; Chiang et al, 2009; Bartsch et al, 2010; Tajir et al, 2013; De Vries et al, 2016)

Summary

Introduction

Rubinstein-Taybi syndrome (RSTS) is a rare genetic syndrome featuring distinctive facial dysmorphisms, characteristic hand and foot findings, short stature, developmental delay, and intellectual disability, with a reported incidence of 1:100,000–1:125,000 births in the Netherlands (Hennekam et al, 1990; Wiley et al, 2003; Hennekam, 2006). It has been reported that routine exome sequencing (ES) variant calling pipelines are unable to detect variants with VAFs lower than 10% (Gambin et al, 2020). It might be questioned whether some of the previously reported, presumed DNVs in probands might derive from parents with unidentified low-level somatic and/or germline mosaicism (Jonsson et al, 2018; Hu et al, 2019; Gambin et al, 2020). With the use of trio whole-exome sequencing (WES), we detected a novel CREBBP variant in the two children; subsequent high-depth NGS identified a mosaic variant in the mother, indicating low-level maternal germline mosaicism (

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Conclusion