Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.
Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.
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DOI：
10.1002/ajmg.a.37942
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发表时间：
2016-12
影响因子：
2
通讯作者：
Cohn, Daniel H.
中科院分区：
文献类型：
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作者：
Weinstein, Michael M.;Kang, Taekyu;Lachman, Ralph S.;Bamshad, Michael;Nickerson, Deborah A.;Krakow, Deborah;Cohn, Daniel H.
编码瞬时受体潜势阳离子通道V亚家族4钙通道的TRPV4基因的显性突变导致一系列肌肉骨骼疾病，包括一系列周围神经疾病和广泛的骨骼发育不良表型谱。骨骼表型的范围从有轻度矮小的脊柱侧弯的短小到围产期致死性化生发育不良。我们描述了一个病例，其表型发现与化生异型增生一致，但通过Sanger序列分析没有检测到TRPV4突变。外显子序列分析确定了一个已知的致死性化生异型增生突变，TRPV4L618P，其出现的频率低于杂合子变化的预期。受影响的个体被证明是该突变的体细胞嵌合体，这为比预期更温和的表型提供了解释。这些数据表明，基因组DNA的高通量测序可以比Sanger序列分析更敏感地检测嵌合体，并发现化生异型增生的新的遗传机制。
Dominant mutations in TRPV4, which encodes the Transient Receptor Potential Cation Channel Subfamily V Member 4 calcium channel, result in a series of musculoskeletal disorders that include a set of peripheral neuropathies and a broad phenotypic spectrum of skeletal dysplasias. The skeletal pheno-types range from brachyolmia, in which there is scoliosis with mild short stature, through perinatal lethal metatropic dysplasia. We describe a case with phenotypic findings consistent with metatropic dysplasia, but in whom no TRPV4 mutation was detected by Sanger sequence analysis. Exome sequence analysis identified a known lethal metatropic dysplasia mutation, TRPV4L618P, which was present at lower frequency than would be expected for a heterozygous change. The affected individual was shown to be a somatic mosaic for the mutation, providing an explanation for the milder than expected phenotype. The data illustrate that high-throughput sequencing of genomic DNA can facilitate detection of mosaicism with higher sensitivity than Sanger sequence analysis and identify a new genetic mechanism for metatropic dysplasia.
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