Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
All Wales Medical Genomics Service, Cardiff, United Kingdom.
Genet Med. 2021 May;23(5):881-887. doi: 10.1038/s41436-020-01076-8. Epub 2021 Jan 20.
Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.
Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.
We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.
This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
神经发育障碍（NDD）包括一系列具有共同特征的遗传异质性疾病，这些特征通常包括发育迟缓、智力障碍和自闭症谱系障碍。我们试图描绘由 GNAI1 基因变异引起的新型神经发育障碍的分子和表型谱。
通过大型队列三体型外显子组测序和国际数据共享，我们鉴定了 24 名具有 NDD 表型和 GNAI1 变异的无关联个体，该基因编码异三聚体 G 蛋白的抑制性 Gαi1 亚基。我们收集了每位受影响个体的详细基因型和表型信息。
我们在 24 名受影响个体中鉴定出了 GNAI1 中的 16 个独特变异；23 个是新生的，1 个是从镶嵌型父母遗传的。大多数受影响的个体患有严重的神经发育障碍。核心特征包括全面发育迟缓、智力障碍、低张力和癫痫。
这项合作确立了 GNAI1 变异是 NDD 的原因之一。GNAI1 相关的 NDD 通常以严重至重度发育迟缓、低张力、从自限性到难治性癫痫、行为问题和可变的轻度畸形特征为特征。
