Abdel-Hamid Mohamed S, Paimboeuf Adeline, Zaki Maha S, Figueiredo Fernanda, Abdel-Ghafar Sherif F, Maher Sabrina, Friðriksdóttir Rún, Sulem Patrick, Högnason Hákon Björn, Hallgrímsdóttir Sigrún, Rojas Catarina Falleiros N, Kok Fernando, Suri Mohnish, Alves César Augusto P F, Houlden Henry, Maroofian Reza, Patten Shunmoogum A
Medical Molecular Genetics Department, National Research Centre, Human Genetics and Genome Research Institute, Cairo 12622, Egypt.
Centre Armand Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique (INRS), Laval, QC, Canada H7V 1B7.
Brain Commun. 2025 Feb 5;7(1):fcaf055. doi: 10.1093/braincomms/fcaf055. eCollection 2025.
RNA polymerase III transcribes essential non-coding RNAs, a process regulated by transcription factors TFIIIB and TFIIIC. Although germline variants in TFIIIC subunit genes have been described in a few patients with neurodevelopmental disorders, the associated pathogenesis and clinical spectrum are not yet well defined. Herein, we describe the identification of biallelic variants in which encodes a key component of the TFIIIC subunit, in four patients from three unrelated families of different ethnicities collected through GeneMatcher. The patients exhibited microcephaly, developmental delay, intellectual disability and distinctive dysmorphic facies that appear recognizable in very young children. Their brain imaging showed brain atrophy with predominant cerebellar involvement, as well as hypoplasia of the frontal lobes and one patient had moderate to severe simplified gyral pattern. Seizures were observed in half of the patients. Exome/genome sequencing revealed four different variants including three missense (p.Cys172Gly, p.Val427Phe and p.Ala509Thr) and one nonsense variant (p.Arg717Ter). Missense variants were not present in known genetic databases and occurred in highly conserved residues. Knockout of the ortholog in zebrafish recapitulated the key clinical symptoms including microcephaly, brain anomalies and seizure susceptibility. We also observed reduced RNA polymerase III target gene expression in the zebrafish knockout model. This study describes a new neurodevelopmental syndrome in humans and zebrafish associated with biallelic variants and underscores the need for further research into the biological impacts of variants in TFIIIC-linked genes and their contribution to RNA polymerase III-related pathologies.
RNA聚合酶III转录必需的非编码RNA，这一过程由转录因子TFIIIB和TFIIIC调控。尽管在少数神经发育障碍患者中已描述了TFIIIC亚基基因的种系变异，但其相关的发病机制和临床谱尚未明确界定。在此，我们描述了通过GeneMatcher收集的来自三个不同种族的三个无关家庭的四名患者中，编码TFIIIC亚基关键成分的基因的双等位基因变异的鉴定。这些患者表现出小头畸形、发育迟缓、智力残疾和独特的畸形面容，在幼儿期即可识别。他们的脑部影像学显示脑萎缩，主要累及小脑，以及额叶发育不全，一名患者有中度至重度简化脑回模式。一半的患者观察到癫痫发作。外显子组/基因组测序揭示了四种不同的变异，包括三种错义变异（p.Cys172Gly、p.Val427Phe和p.Ala509Thr）和一种无义变异（p.Arg717Ter）。错义变异在已知的遗传数据库中不存在，且发生在高度保守的残基中。斑马鱼中该直系同源基因的敲除重现了关键的临床症状，包括小头畸形、脑异常和癫痫易感性。我们还在斑马鱼敲除模型中观察到RNA聚合酶III靶基因表达降低。本研究描述了一种与双等位基因变异相关的人类和斑马鱼新的神经发育综合征，并强调需要进一步研究TFIIIC相关基因变异的生物学影响及其对RNA聚合酶III相关病理学的贡献。
