Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX 77030, USA.
University of Brasilia, Brasilia 70910, Brazil; Robinow Syndrome Foundation, Anoka, MN 55303, USA.
Am J Hum Genet. 2018 Jan 4;102(1):27-43. doi: 10.1016/j.ajhg.2017.10.002. Epub 2017 Dec 21.
Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.
位置异质性是多种骨骼发育不良的特征，通常是由于相互作用或重叠的信号通路引起的。罗宾诺综合征是一种骨骼疾病，历史上难以进行分子诊断，可能源于大量的遗传异质性。所有当前已知的致病性变异都位于非经典 Wnt 信号通路中的基因中，包括 ROR2、WNT5A，以及最近的 DVL1 和 DVL3。然而，约 70%的常染色体显性遗传罗宾诺综合征病例仍然无法通过分子手段解决。为了研究这一缺失的遗传率，我们招募了 21 个家族，其中至少有一个家族成员被临床诊断为罗宾诺或罗宾诺样表型，并进行了遗传和基因组研究。总共鉴定出四个家族存在 FZD2 变异，以及两个家族的三个个体存在 NXN 的双等位基因变异，这些变异与表型共分离。重要的是，FZD2 和 NXN 都是 WNT5A 相互作用组中的相关蛋白伴侣，支持它们在骨骼发育中的作用。除了证实 DVL1 和 DVL3 中的簇-1 移码变异是显性罗宾诺综合征的主要原因外，我们还在候选基因 GPC4 和 RAC3 中发现了可能的致病性变异，这两个基因都与 Wnt 信号通路有关。这些数据支持了一个初步假设，即罗宾诺综合征是由于 Wnt/PCP 通路的扰动引起的，提示了涉及的蛋白质的特定相关结构域，并揭示了人类胚胎发育过程中该信号级联中的关键贡献者。本研究与非等位基因遗传异质性阻碍基因发现的观点相反，证明了罕见病基因组研究在解析人类发育途径中的基因功能方面的实用性。
