Structural variation and missense mutation in SBDSassociated with Shwachman-Diamond syndrome

BMC Medical Genetics

Case Report

Nicholas J Neill¹  Luciana W Zuccherato¹  Claudia M B Carvalho²  Alison A Bertuch³  James R Lupski³  Christopher L Williams⁴  Matthew Bainbridge⁵  David R Murdock⁵  Shalini N Jhangiani⁵  Donna M Muzny⁵  Richard A Gibbs⁵  Wan Ip⁶  Robert Paul Guillerman⁷ 

[1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;Centro de Pesquisas René Rachou – FIOCRUZ, Belo Horizonte, MG, Brazil;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;Texas Children’s Hospital, 1102 Bates, FC 1200, 77030, Houston, TX, USA;Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA;Program in Physiology and Experimental Medicine, The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada;Texas Children’s Hospital, 1102 Bates, FC 1200, 77030, Houston, TX, USA;Department of Radiology, Baylor College of Medicine, Houston, TX, USA;

关键词: Shwachman-Diamond syndrome;    SBDS;    Structural variation;    Genomic rearrangement;    Non-allelic homologous recombination;    Low copy repeat;    Whole exome sequencing;    Copy number variation;    Recessive disease;   

DOI  :  10.1186/1471-2350-15-64

 received in 2014-03-13, accepted in 2014-05-29,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundShwachman–Diamond syndrome (SDS) is an autosomal recessive ribosomopathy caused mainly by compound heterozygous mutations in SBDS. Structural variation (SV) involving the SBDS locus has been rarely reported in association with the disease. We aimed to determine whether an SV contributed to the pathogenesis of a case lacking biallelic SBDS point mutations.Case presentationWhole exome sequencing was performed in a patient with SDS lacking biallelic SBDS point mutations. Array comparative genomic hybridization and Southern blotting were used to seek SVs across the SBDS locus. Locus-specific polymerase chain reaction (PCR) encompassing flanking intronic sequence was also performed to investigate mutation within the locus. RNA expression and Western blotting were performed to analyze allele and protein expression. We found the child harbored a single missense mutation in SBDS (c.98A > C; p.K33T), inherited from the mother, and an SV in the SBDS locus, inherited from the father. The missense allele and SV segregated in accordance with Mendelian expectations for autosomal recessive SDS. Complementary DNA and western blotting analysis and locus specific PCR support the contention that the SV perturbed SBDS protein expression in the father and child.ConclusionOur findings implicate genomic rearrangements in the pathogenesis of some cases of SDS and support patients lacking biallelic SBDS point mutations be tested for SV within the SBDS locus.

【 授权许可】

Unknown   
© Carvalho et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.