Ying Zhao, Yiyang Fu, Shuying Zhang, Yuxin Han, Jinhui Zhu, Wanqi Liu, Shuxian Li, Dan Xiao, Yuan Liu, Lin Wang, Ruixue Zhang, Wenjing Cheng, Kaitao Ren, Xiaorui Zhang, Mingyue Chen, Abdullah, Umm-E- Kalsoom, Nousheen Bibi, Saadullah Khan, Fengni Fan, Ting Jia, Xiangdong Lin, Wei Li, Zhao Li, Gen Nishimura, Takahiro Yamada, Na Cai, Chisa Shukunami, Zhiqiang Tian, Xiaoxu Chen, Shiro Ikegawa, Rong Qiang, Long Guo
Genetic analysis identified two compound heterozygous CDC45 variants: c.1416C>T (p.H472=) and c.1559+2T>A, which are a recurrent variant in the East Asian population and a novel variant, respectively. Our exon-trapping assay indicated that c.1559+2T>A induced aberrant splicing, generating transcripts predicted to undergo nonsense-mediated mRNA decay. Additionally, growth hormone therapy was initiated in our patient, with a noted improvement in growth parameters in the initial assessment and without immediate complications. The literature review identified a total of 32 CDC45 variants in 29 patients with MGORS7, who showed high heterogeneity in clinical phenotypes.
INTRODUCTION: Meier-Gorlin syndrome 7 (MGORS7) is a rare autosomal recessive disorder characterized by primordial dwarfism, craniosynostosis, and patellar aplasia, caused by pathogenic variants of CDC45. Here, we report a Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments.
METHODS: Clinical and radiological data were collected. Whole-genome sequencing and Sanger sequencing were performed to identify and validate the causative variants. Their functional effects were investigated using an exon-trapping assay, and a literature review of previously reported MGORS7 cases was conducted.
RESULTS: Genetic analysis identified two compound heterozygous CDC45 variants: c.1416C>T (p.H472=) and c.1559+2T>A, which are a recurrent variant in the East Asian population and a novel variant, respectively. Our exon-trapping assay indicated that c.1559+2T>A induced aberrant splicing, generating transcripts predicted to undergo nonsense-mediated mRNA decay. Additionally, growth hormone therapy was initiated in our patient, with a noted improvement in growth parameters in the initial assessment and without immediate complications. The literature review identified a total of 32 CDC45 variants in 29 patients with MGORS7, who showed high heterogeneity in clinical phenotypes.
DISCUSSION: Our study further expanded the mutational spectrum of CDC45 and provided a preliminary clinical observation suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.