Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
BMC Neurol. 2021 Sep 16;21(1):358. doi: 10.1186/s12883-021-02380-9.
Pathogenic variants in KDM5C are a cause of X-linked intellectual disability in males. Other features in males include short stature, dysmorphic features, seizures and spasticity. In some instances, female relatives were noted to have learning difficulties and mild intellectual disabilities, but full phenotypic descriptions were often incomplete. Recently, detailed phenotypic features of five affected females with de novo variants were described. (Clin Genet 98:43-55, 2020) Four individuals had a protein truncating variant and 1 individual had a missense variant. All five individuals had developmental delay/intellectual disability and three neurological features.
Here we report a three-year-old female with global developmental delay, hypotonia and ataxia. Through whole exome sequencing, a de novo c.1516A > G (p.Met506Val) variant in KDM5C was identified. This missense variant is in the jumonji-C domain of this multi domain protein where other missense variants have been previously reported in KDM5C related disorder. The KDM5C gene is highly intolerant to functional variation which suggests its pathogenicity. The probands motor delays and language impairment is consistent with other reported female patients with de novo variants in KDM5C. However, other features reported in females (distinctive facial features, skeletal abnormalities, short stature and endocrine features) were absent. To the best of our knowledge, our proband is the first female patient reported with a diagnosis of ataxia.
This case report provides evidence for an emerging and phenotypic variability that adds to the literature of the role of KDM5C in females with neurodevelopmental disorders as well as movement disorders.
KDM5C 的致病性变异是导致男性 X 连锁智力障碍的原因。男性的其他特征包括身材矮小、畸形特征、癫痫发作和痉挛。在某些情况下，女性亲属被注意到有学习困难和轻度智力障碍，但完整的表型描述往往不完整。最近，描述了五名新发变异的受影响女性的详细表型特征。（临床遗传学 98:43-55, 2020）四名个体有蛋白质截断变异，一名个体有错义变异。所有五名个体均有发育迟缓/智力障碍和三种神经特征。
这里我们报告了一名三岁女性，表现为全面发育迟缓、低张力和共济失调。通过全外显子组测序，发现 KDM5C 中存在一个 c.1516A > G (p.Met506Val) 的新生变异。该错义变异位于该多功能蛋白的 jumonji-C 结构域，先前在 KDM5C 相关疾病中已有其他错义变异的报道。KDM5C 基因对功能变异高度不耐受，提示其致病性。先证者的运动发育迟缓及语言障碍与其他报道的新发变异 KDM5C 女性患者一致。然而，其他在女性中报道的特征（独特的面部特征、骨骼异常、身材矮小和内分泌特征）不存在。据我们所知，我们的先证者是第一个被诊断为共济失调的女性患者。
本病例报告提供了证据，证明了 KDM5C 在伴有神经发育障碍和运动障碍的女性中的作用的新出现和表型变异性，增加了文献证据。
