TY - JOUR

T1 - The effect of a single SMARCA4 exon deletion on RNA splicing

T2 - Implications for variant classification

AU - Byrjalsen, Anna

AU - Stoltze, Ulrik

AU - Mehrjouy, Mana

AU - Frederiksen, Jane Hübertz

AU - Bak, Mads

AU - Birkedal, Ulf

AU - Hasle, Henrik

AU - Gerdes, Anne-Marie

AU - Schmiegelow, Kjeld

AU - Wadt, Karin

AU - Hansen, Thomas van Overeem

N1 - Publisher Copyright: © 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

PY - 2023

Y1 - 2023

N2 - Background: 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. Methods: 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. Results: 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. Conclusion: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusion: 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.

KW - de novo

KW - single-exon deletion

KW - small cell carcinoma of the ovary

KW - SMARCA4

KW - splicing

KW - variant classification

U2 - 10.1002/mgg3.2232

DO - 10.1002/mgg3.2232

M3 - Journal article

C2 - 37430472

AN - SCOPUS:85164669930

VL - 11

JO - Molecular genetics & genomic medicine

JF - Molecular genetics & genomic medicine

SN - 2324-9269

IS - 10

M1 - e2232

ER -