Department of Molecular Medicine and Surgery (MMK), Karolinska Institute, Stockholm, Sweden.
Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
J Med Genet. 2022 Feb;59(2):141-146. doi: 10.1136/jmedgenet-2020-107385. Epub 2020 Nov 18.
Germline pathogenic variants in cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (lobal developmental delay, ung cysts, vergrowth, ilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.
Whole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with RNase III domain mutations were performed.
A de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome.
The phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to hotspot mutations in the RNase IIIb domain. We show that an individual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome ('DICER1 syndrome plus'), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.
胚系致病性变异会导致 DICER1 综合征，这是一种常染色体显性遗传的多效性肿瘤易感性综合征，具有不同的表现度和特定发育不良和肿瘤病变的低外显率。最近，在两个 DICER1 RNase IIIb 结构域热点残基存在镶嵌性错义突变的儿童中，描述了一种具有缩写 GLOW（整体发育迟缓、肺囊肿、过度生长、肺母细胞瘤）的综合征。
进行了全基因组测序、外显子组测序、Sanger 测序、数字 PCR，并对具有 RNase III 结构域突变的肾母细胞瘤进行了回顾性分析。
在编码 DICER1 RNase IIIa 结构域的序列中发现了一个新的杂合 c.4031C>T（p.S1344L）变异。临床研究显示出一种与 GLOW 综合征表型相似的表型。
p.S1344L 突变患者与 GLOW 综合征之间的表型重叠为最近的发现提供了临床支持，即 RNase IIIa-Ser1344 位点突变类似于 RNase IIIb 结构域中的热点突变，阻碍了 miRNA-5p 的生物发生。我们表明，具有杂合性胚系 p.S1344L 突变的个体具有严重的 DICER1 综合征（“DICER1 综合征+”），具有明显的智力残疾、大头畸形、身体异常、肾母细胞瘤和分化良好的肺胎儿腺癌的特征。
