Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Department of Biology, University of Virginia, Charlottesville, Virginia, USA.
BMJ Case Rep. 2021 Jan 18;14(1):e236732. doi: 10.1136/bcr-2020-236732.
Pontocerebellar hypoplasia type 1B (PCH1B) describes an autosomal recessive neurological condition that involves hypoplasia or atrophy of the cerebellum and pons, resulting in neurocognitive impairments. Although there is phenotypic variability, this is often an infantile lethal condition, and most cases have been described to be congenital and neurodegenerative. PCH1B is caused by mutations in the gene EXOSC3, which encodes exosome component 3, a subunit of the human RNA exosome complex. A range of pathogenic variants with some correlation to phenotype have been reported. The most commonly reported pathogenic variant in EXOSC3 is c.395A>C, p.(Asp132Ala); homozygosity for this variant has been proposed to lead to milder phenotypes than compound heterozygosity. In this case, we report two siblings with extraordinarily mild presentations of PCH1B who are compound heterozygous for variants in EXOSC3 c.155delC and c.80T>G. These patients drastically expand the phenotypic variability of PCH1B and raise questions about genotype-phenotype associations.
1B 型桥小脑发育不良（PCH1B）描述了一种常染色体隐性神经疾病，涉及小脑和脑桥的发育不良或萎缩，导致神经认知障碍。尽管存在表型变异性，但这通常是一种婴儿致死性疾病，大多数病例被描述为先天性和神经退行性的。PCH1B 是由 EXOSC3 基因突变引起的，该基因编码外泌体成分 3，是人 RNA 外泌体复合物的一个亚基。已经报道了一系列与表型有一定相关性的致病性变异体。EXOSC3 中最常报道的致病性变异体是 c.395A>C，p.(Asp132Ala)；该变异体的纯合性被认为比复合杂合性导致更温和的表型。在这种情况下，我们报告了两例 PCH1B 的同胞患者，他们均为 EXOSC3 c.155delC 和 c.80T>G 变异的复合杂合子。这些患者极大地扩展了 PCH1B 的表型变异性，并提出了关于基因型-表型相关性的问题。
