Exome Sequencing Identifies an MYH3 Mutation in a Family with Distal Arthrogryposis Type 1
Exome Sequencing Identifies an MYH3 Mutation in a Family with Distal Arthrogryposis Type 1
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DOI：
10.2106/jbjs.j.02004
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发表时间：
2011-06-01
影响因子：
5.3
通讯作者：
Dobbs, Matthew B.
中科院分区：
文献类型：
--
作者：
Alvarado, David M.;Buchan, Jillian G.;Dobbs, Matthew B.
背景资料：虽然编码肌节蛋白质的基因与其他类型的远端关节弯曲有关，但很少有基因与1型远端关节弯曲有关。具有成本效益的测序方法，现在可以检查所有的基因在人类基因组中的目的，建立的遗传基础的肌肉骨骼disorders.Methods：一个多代家庭远端arthrogriposis 1型，其特征在于马蹄内翻足和轻度手挛缩被确定，和外显子组测序进行DNA从受影响的家庭成员之一。连锁分析被用来确认是否与远端arthrogriposis.Results的遗传变异隔离：外显子组测序确定了573个新的变异，不存在于控制数据库。MYH 3（编码肌球蛋白重链的基因）中的错义突变导致F437 I氨基酸取代，被鉴定为与该家族中的远端关节弯曲症分离。连锁分析证实，这MYH 3突变是唯一的外显子组变异共同所有六个受影响的individual.Conclusions：在这个家庭与远端arthrogriposis 1型MYH 3突变的鉴定拓宽了与MYH 3突变相关的表型，包括远端arthrogriposis类型1，2A（弗里曼-谢尔登综合征），和2B（谢尔登-霍尔综合征）。外显子组测序是发现致病基因突变的一种有用且具有成本效益的方法，尽管可能需要来自大家族的数据来确认数百种已鉴定变体的重要性。
Background: Few genes responsible for distal arthrogryposis type 1 are known, although genes coding for the proteins in the sarcomere have been implicated in other types of distal arthrogryposis. Cost-effective sequencing methods are now available to examine all genes in the human genome for the purpose of establishing the genetic basis of musculoskeletal disorders.Methods: A multigenerational family with distal arthrogryposis type 1 characterized by clubfoot and mild hand contractures was identified, and exome sequencing was performed on DNA from one of the affected family members. Linkage analysis was used to confirm whether a genetic variant segregated with distal arthrogryposis.Results: Exome sequencing identified 573 novel variants that were not present in control databases. A missense mutation in MYH3 (a gene coding for the heavy chain of myosin), causing an F437I amino acid substitution, was identified that segregated with distal arthrogryposis in this family. Linkage analysis confirmed that this MYH3 mutation was the only exome variant common to all six affected individuals.Conclusions: Identification of an MYH3 mutation in this family with distal arthrogryposis type 1 broadens the phenotype associated with MYH3 mutations to include distal arthrogryposis types 1, 2A (Freeman-Sheldon syndrome), and 2B (Sheldon-Hall syndrome). Exome sequencing is a useful and cost-effective method to discover causative genetic mutations, although data from extended families may be needed to confirm the importance of the hundreds of identified variants.