Byrjalsen Anna, Stoltze Ulrik, Mehrjouy Mana, Frederiksen Jane Hübertz, Bak Mads, Birkedal Ulf, Hasle Henrik, Gerdes Anne-Marie, Schmiegelow Kjeld, Wadt Karin, Hansen Thomas van Overeem
Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Mol Genet Genomic Med. 2023 Oct;11(10):e2232. doi: 10.1002/mgg3.2232. Epub 2023 Jul 10.
Exon deletions are generally considered pathogenic, particularly when they are located out of frame. Here, we describe a pediatric, female patient presenting with hypercalcemia and a small cell carcinoma of the ovary, hypercalcemic type, and carrying a germline de novo SMARCA4 exon 14 deletion.
The SMARCA4 deletion was identified by whole genome sequencing, and the effect on the RNA level was examined by gel- and capillary electrophoresis and nanopore sequencing.
The deletion was in silico predicted to be truncating, but RNA analysis revealed two major transcripts with deletion of exon 14 alone or exon 14 through 15, where the latter was located in-frame. Because the patient's phenotype matched that of other patients with pathogenic germline variants in SMARCA4, the deletion was classified as likely pathogenic.
We propose to include RNA analysis in classification of single-exon deletions, especially if located outside of known functional domains, as this can identify any disparate effects on the RNA and DNA level, which may have implications for variant classification using the American College of Medical Genetics and Genomics guidelines.
外显子缺失通常被认为是致病性的，特别是当它们位于框外时。在此，我们描述了一名患有高钙血症和卵巢高钙血症型小细胞癌的儿科女性患者，其携带种系新发SMARCA4外显子14缺失。
通过全基因组测序鉴定出SMARCA4缺失，并通过凝胶电泳、毛细管电泳和纳米孔测序检测其对RNA水平的影响。
该缺失在计算机模拟中预测会导致截短，但RNA分析显示有两种主要转录本，一种仅缺失外显子14，另一种缺失外显子14至15，后者位于读码框内。由于该患者的表型与其他具有SMARCA4致病性种系变异的患者相符，因此该缺失被分类为可能致病。
我们建议在单外显子缺失的分类中纳入RNA分析，特别是当缺失位于已知功能域之外时，因为这可以识别对RNA和DNA水平的任何不同影响，这可能对根据美国医学遗传学与基因组学学会指南进行变异分类有影响。
