Macmurdo Colleen F, Wooderchak-Donahue Whitney, Bayrak-Toydemir Pinar, Le Jenny, Wallenstein Matthew B, Milla Carlos, Teng Joyce M C, Bernstein Jonathan A, Stevenson David A
Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, California.
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.
Am J Med Genet A. 2016 Jun;170(6):1450-4. doi: 10.1002/ajmg.a.37613. Epub 2016 Mar 11.
Germline mutations in RASA1 are associated with capillary malformation-arteriovenous malformation (CM-AVM) syndrome. CM-AVM syndrome is characterized by multi-focal capillary malformations and arteriovenous malformations. Lymphatic anomalies have been proposed as part of the phenotype. Intrafamilial variability has been reported, suggesting modifiers and somatic events. The objective of the study was to identify somatic RASA1 "second hits" from vascular malformations associated with CM-AVM syndrome, and describe phenotypic variability. Participants were examined and phenotyped. Genomic DNA was extracted from peripheral blood on all participants. Whole-exome sequencing was performed on the proband. Using Sanger sequencing, RASA1 exon 8 was PCR-amplified to track the c.1248T>G, p.Tyr416X germline variant through the family. A skin biopsy of a capillary malformation from the proband's mother was also obtained, and next-generation sequencing was performed on DNA from the affected tissue. A familial germline heterozygous novel pathogenic RASA1 variant, c.1248T>G (p.Tyr416X), was identified in the proband and her mother. The proband had capillary malformations, chylothorax, lymphedema, and overgrowth, while her affected mother had only isolated capillary malformations. Sequence analysis of DNA extracted from a skin biopsy of a capillary malformation of the affected mother showed a second RASA1 somatic mutation (c.2245C>T, p.Arg749X). These results and the extreme variable expressivity support the hypothesis that somatic "second hits" are required for the development of vascular anomalies associated with CM-AVM syndrome. In addition, the phenotypes of the affected individuals further clarify that lymphatic manifestations are also part of the phenotypic spectrum of RASA1-related disorders. © 2016 Wiley Periodicals, Inc.
RASA1基因的种系突变与毛细血管畸形 - 动静脉畸形（CM - AVM）综合征相关。CM - AVM综合征的特征为多灶性毛细血管畸形和动静脉畸形。淋巴管异常已被认为是该综合征表型的一部分。有家族内变异性的报道，提示存在修饰基因和体细胞事件。本研究的目的是从与CM - AVM综合征相关的血管畸形中鉴定RASA1基因的体细胞“二次打击”，并描述表型变异性。对参与者进行了检查并确定其表型。从所有参与者的外周血中提取基因组DNA。对先证者进行全外显子组测序。使用桑格测序法，对RASA1基因第8外显子进行PCR扩增，以追踪家系中c.1248T>G、p.Tyr416X种系变异。还获取了先证者母亲的毛细血管畸形皮肤活检样本，并对受累组织的DNA进行了二代测序。在先证者及其母亲中鉴定出一种家族性种系杂合新型致病性RASA1变异，即c.1248T>G（p.Tyr416X）。先证者有毛细血管畸形、乳糜胸、淋巴水肿和过度生长，而其受累母亲仅有孤立的毛细血管畸形。对受累母亲的毛细血管畸形皮肤活检样本提取的DNA进行序列分析，显示存在第二个RASA1体细胞突变（c.2245C>T，p.Arg749X）。这些结果以及极端的可变表达性支持了这样的假说，即体细胞“二次打击”是与CM - AVM综合征相关的血管异常发生所必需的。此外，受累个体的表型进一步明确，淋巴系统表现也是RASA1相关疾病表型谱的一部分。© 2016威利期刊公司
