Heterozygous WNT1 variant causing a variable bone phenotype
Heterozygous WNT1 variant causing a variable bone phenotype
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DOI：
10.1002/ajmg.a.40347
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发表时间：
2018-11-01
影响因子：
2
通讯作者：
Bird, Lynne M.
中科院分区：
文献类型：
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作者：
Alhamdi, Shatha;Lee, Yi-Chien;Bird, Lynne M.
成骨不全(OI)是一类遗传性骨脆性疾病。大多数OI患者都有编码I型胶原的基因突变；至少还有17个其他基因与OI有关。WNT1双等位基因功能丧失突变导致严重OI。WNT1基因杂合性错义变异是早发性骨质疏松症的原因，其骨表型多种多样。在此，我们报告了一个有四个患者的第三代家庭，其中一些人在童年时表现为多发性低冲击性骨折，另一些人表现为早发性骨质疏松症，没有显著的骨折病史。在先证者中发现了WNT1变异(c.1051>；C；p.Trp351Arg)，并在另外三个家系成员中分离出骨表型，符合常染色体显性遗传。在先证者中，全基因组测序还发现了22q11.2的从头复制(434kb)，涉及25个基因，其中4个与单倍体不足时的人类疾病有关。虽然比典型的(1.5Mb)22q11.2重复较小，但先证者的重复可能是其表型的其他非骨性方面(肌张力低下、发育迟缓、生殖器小、斜视和青春期前抑郁)的原因。该病例证实了WNT1变异导致的骨表型的多样性，并扩大了与WNT1杂合突变相关的骨表型的范围。
Osteogenesis imperfecta (OI) is a family of heritable disorders of bone fragility. Most individuals with OI have mutations in the genes encoding type I collagen; at least 17 other genes have been associated with OI. Biallelic loss-of-function mutations in WNT1 cause severe OI. Heterozygous missense variants in WNT1 are responsible for early-onset osteoporosis with variable bone phenotypes. Herein, we report a third-generation family with four affected individuals, some presenting with multiple low-impact fractures in childhood and others presenting with early-onset osteoporosis without a striking fracture history. A WNT1 variant (c.1051 > C; p.Trp351Arg) was identified in the proband and segregated with a bone phenotype in three additional family members, consistent with autosomal dominant inheritance. In the proband, whole genome sequencing also revealed a de novo duplication (434 kb) of 22q11.2 that involves 25 genes, 4 of which are associated with human disease when haploinsufficient. Though smaller than the typical (1.5 Mb) 22q11.2 duplication, the duplication in the proband may be responsible for additional non-osseous aspects of his phenotype (hypotonia, developmental delay, small genitalia, strabismus, and depression in preadolescence). This case demonstrates the variability of bone phenotype conferred by a WNT1 variant and extends the spectrum of bone phenotypes associated with heterozygous WNT1 mutations.