Neonatal progeroid syndrome, also known as Wiedemann–Rautenstrauch syndrome, is a rare condition characterized by severe growth retardation, apparent macrocephaly with prominent scalp veins, and lipodystrophy. It is caused by biallelic variants in POLR3A, a gene encoding for a subunit of the RNA polymerase III. All variants reported in the literature lead to at least a partial loss-of-function (when considering both alleles together). Here, we describe an individual with several clinical features of neonatal progeroid syndrome in whom exome sequencing revealed a homozygous nonsense variant in POLR3GL (NM_032305.2:c.358C>T; p.(Arg120Ter)). POLR3GL also encodes a subunit of RNA polymerase III and has recently been associated with endosteal hyperostosis and oligodontia in three patients with a phenotype distinct from the patient described here. Given the important role of POLR3GL in the same complex as the protein implicated in neonatal progeroid syndrome, the nature of the variant identified, our RNA studies suggesting nonsense-mediated decay, and the clinical overlap, we propose POLR3GL as a gene causing a variant of neonatal progeroid syndrome and therefore expand the phenotype associated with POLR3GL variants.

新生儿早衰综合征，也称为 Wiedemann-Rautenstrauch 综合征，是一种罕见的疾病，其特征是严重的生长迟缓、明显的大头畸形伴明显的头皮静脉和脂肪营养不良。它是由 POLR3A 中的双等位基因变异引起的，POLR3A是一种编码 RNA 聚合酶 III 亚基的基因。文献中报道的所有变体都会导致至少部分功能丧失（当同时考虑两个等位基因时）。在这里，我们描述了一个具有新生儿早衰综合征几个临床特征的个体，其中外显子组测序揭示了 POLR3GL 中的纯合无义变体( NM_032305.2 :c.358C>T; p.(Arg120Ter))。POLR3GL还编码 RNA 聚合酶 III 的一个亚基，并且最近与三名具有与此处描述的患者不同表型的患者的骨内膜肥厚和少牙症有关。鉴于POLR3GL在与涉及新生儿早衰综合征的蛋白质相同的复合物中的重要作用、变异的性质已确定、我们的 RNA 研究表明无意义介导的衰变以及临床重叠，我们提出POLR3GL作为导致新生儿早衰综合征，因此扩大了与POLR3GL变体相关的表型。