Variable skeletal phenotypes associated with biallelic variants in PRKG2.
Variable skeletal phenotypes associated with biallelic variants in PRKG2.
复制标题
prkg2中与双重变体相关的可变骨骼表型。
DOI：
10.1136/jmedgenet-2021-108027
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发表时间：
2022-10
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
100 000 基因组计划 (100KGP) 是一项全英国范围内的计划，其目标是利用全基因组测序 (WGS) 来识别罕见遗传病的遗传原因，并将该技术纳入 NHS 中。 1 利用该资源的数据以及国际基因匹配工作，发现来自两个独立家族的四名个体携带 PRKG2（一种最近描述的骨骼发育不良基因）纯合移码或停止增益变异。 2 详细的临床和放射学评估有助于扩大与这种常染色体隐性遗传疾病相关的表型范围，而功能研究表明这两种变异对 FGF 诱导的 MAPK 信号传导具有相似的影响。 PRKG2 编码环鸟苷单磷酸依赖性蛋白激酶 II (cGKII)，其作用于利尿钠肽受体 B/C-利尿钠肽 (NPR-B/CNP) 的下游。 NPR-B 由 NPR2 编码，双等位变体导致顶体发育不良，Maroteaux 型（AMDM；MIM 602875）。啮齿动物模型进一步表明 PRKG2 参与骨骼发育 3 4 并且 cGKII 缺陷被证明是在安格斯牛中观察到的侏儒症表型的原因。 5 基于通路分析和模型生物的支持，最近的一项研究表明，双等位基因 PRKG2 变异可导致人类顶体发育不良、PRKG2 型 (AMDP)，2 将 PRKG2 添加到与遗传性骨骼疾病相关的超过 400 个基因的列表中。 6 由于仅报告了两名受影响的个体，因此描述这种情况的完整临床范围非常重要。在这项研究中，我们通过 Genomic England 研究环境中提供的 LabKey 应用程序，使用来自 100KGP 的数据搜索罕见的双等位基因 PRKG2 变体。研究人员可以在线申请访问（www.genomesengland.co.uk/join-a-gecip-domain）。初始过滤采用基于 1000 个基因组计划的数据以及内部频率信息的 1% 群体等位基因频率阈值。通过合作者网络鉴定了另一个家族，并使用 ACMG 标准对变异进行了分类（在线补充表 1）。在家族 1 中，WGS 和随后的 Sanger 测序发现了纯合致病性 PRKG2 变异 NM_006259。 3：c。 2282dup（第 Asp-761Glufs* 34；在线补充图 1），三名患有脊椎干骺端发育不良的兄弟（图 1A）。有趣的是，中间受影响的兄弟（F1-IV-6）也患有I型成骨不全症（OI）。一项早期临床外显子组测序研究发现，在 4.6% 的分子诊断病例中，不止一个基因导致了混合表型。 7 此类复杂病例预计在高度血缘关系的家庭中更为常见，其中大面积纯合性区域 (ROH) 构成了基因组的很大一部分；然而，对于 F1-IV-6，OI 的二次诊断是由于 COL1A1 移码造成的，这种移码是从头出现的。由于儿童时期的多处骨折（婴儿时期的手臂、8 岁时的手腕和胸部 T6 楔形骨折）并伴有蓝色巩膜，因此怀疑该儿童患有成骨不全症。当然，共存的 OI 可能对该个体的表型严重程度产生了影响，尤其是因为他的身高比他的两个兄弟更显着降低，而 OI（1 型）本身就是身高降低的已知原因。
The 100 000 Genomes Project (100KGP) is a UK-wide initiative that has a goal of using whole genome sequencing (WGS) to identify genetic causes of rare inherited diseases and embed the use of this technology within the NHS. 1 Using data from this resource alongside international gene-matching efforts, four individuals from two independent families were identified harbouring homozygous frameshift or stop-gain variants in PRKG2, a recently described skeletal dysplasia gene. 2 Detailed clinical and radiological assessments helped extend the phenotypic range associated with this autosomal recessive condition while functional studies indicated that both variants had a similar impact on FGF-induced MAPK signalling. PRKG2 encodes the cyclic guanosine monophosphate dependent protein kinase II (cGKII), which acts downstream of the natriuretic peptide receptor-B/C-natriuretic peptide (NPR-B/CNP). NPR-B is encoded by NPR2, biallelic variants in which are responsible for acromesomelic dysplasia, Maroteaux type (AMDM; MIM 602875). Rodent models further implicate PRKG2 in skeletal development 3 4 and cGKII deficiency was shown to be the cause of the dwarfism phenotype observed in Angus cattle. 5 Building on support from pathway analysis and model organisms, a recent study showed that biallelic PRKG2 variants can result in acromesomelic dysplasia, PRKG2-type (AMDP) in humans, 2 adding PRKG2 to a list of> 400 genes associated with genetic skeletal disorders. 6 As only two affected individuals were reported, it is important that the full clinical range of this condition is described. In this study, we searched for rare biallelic PRKG2 variants using data from the 100KGP via the LabKey application available within Genomic England’s research environment. Researchers can apply for access online (www. genomicsengland. co. uk/join-a-gecip-domain). Initial filtering employed a 1% population allele frequency threshold based on data from the 1000 Genomes Project as well as in-house frequency information. An additional family was identified via a network of collaborators and variants were classified using ACMG criteria (online supplemental table 1).In family 1, WGS and subsequent Sanger sequencing uncovered a homozygous pathogenic PRKG2 variant, NM_006259. 3: c. 2282dup(p. Asp-761Glufs* 34; online supplemental figure 1) in three brothers referred with spondylometaphyseal dysplasia (figure 1A). Interestingly, the middle-affected brother (F1-IV-6) also has type I osteogenesis imperfecta (OI). An early clinical exome sequencing study found that for 4.6% of cases with a molecular diagnosis, more than one gene was contributing to a blended phenotype. 7 Complex cases such as these are expected to be more common in highly consanguineous families where large regions of homozygosity (ROHs) make up a significant proportion of the genome; however, for F1-IV-6 the secondary diagnosis of OI was due to a COL1A1 frameshift, which had arisen de novo. OI was suspected in this child because of multiple fractures in childhood (arm as an infant, wrist aged 8 and thoracic T6 wedge fracture) combined with blue sclerae. It is certainly possible that the coexistent OI may have had an impact on the severity of the phenotype in this individual, not least because his height was more significantly reduced than for his two brothers and OI (type 1) is a known cause of reduced stature in its own right.
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影响因子：
9.8
作者：
Freund, Malika Kumar;Burch, Kathryn S.;Arboleda, Valerie A.
通讯作者：
Arboleda, Valerie A.
DOI：
10.1073/pnas.0904513106
发表时间：
2009-11-17
影响因子：
11.1
作者：
Koltes, James E.;Mishra, Bishnu P.;Reecy, James M.
通讯作者：
Reecy, James M.
DOI：
10.1038/s41436-018-0281-4
发表时间：
2019-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Wakeling MN;Laver TW;Wright CF;De Franco E;Stals KL;Patch AM;Hattersley AT;Flanagan SE;Ellard S;DDD Study
通讯作者：
DDD Study
影响因子：
4
作者：
Diaz-Gonzalez, Francisca;Wadhwa, Saruchi;Heath, Karen E.
通讯作者：
Heath, Karen E.
影响因子：
2
作者：
Wang, Wei;Song, Mi Hyun;Cho, Tae-Joon
通讯作者：
Cho, Tae-Joon