Insights of Noncanonical Splice-site Variants on RNA Splicing in Patients With Congenital Hypothyroidism

Author:

Albader Najla1,Zou Minjing2,BinEssa Huda A2,Abdi Saba1,Al-Enezi Anwar F2,Meyer Brian F2,Alzahrani Ali S3,Shi Yufei2ORCID

Affiliation:

1. Department of Biochemistry, College of Science, King Saud University, Riyadh 11495, Saudi Arabia

2. Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia

3. Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia

Abstract

Abstract Context Congenital hypothyroidism (CH) is caused by mutations in the genes for thyroid hormone synthesis. In our previous investigation of CH patients, approximately 53% of patients had mutations in either coding exons or canonical splice sites of causative genes. Noncanonical splice-site variants in the intron were detected but their pathogenic significance was not known. Objective This work aims to evaluate noncanonical splice-site variants on pre–messenger RNA (pre-mRNA) splicing of CH-causing genes. Methods Next-generation sequencing data of 55 CH cases in 47 families were analyzed to identify rare intron variants. The effects of variants on pre-mRNA splicing were investigated by minigene RNA-splicing assay. Results Four intron variants were found in 3 patients: solute carrier family 26 member 4 (SLC26A4) c.1544+9C>T and c.1707+94C>T in one patient, and solute carrier family 5 member 5 (SLC5A5) c.970-48G>C and c.1652-97A>C in 2 other patients. The c.1707+94C>T and c.970-48G>C caused exons 15 and 16 skipping, and exon 8 skipping, respectively. The remaining variants had no effect on RNA splicing. Furthermore, we analyzed 28 previously reported noncanonical splice-site variants (4 in TG and 24 in SLC26A4). Among them, 15 variants (~ 54%) resulted in aberrant splicing and 13 variants had no effect on RNA splicing. These data were compared with 3 variant-prediction programs (FATHMM-XF, FATHMM-MKL, and CADD). Among 32 variants, FATHMM-XF, FATHMM-MKL, and CADD correctly predicted 20 (63%), 17 (53%), and 26 (81%) variants, respectively. Conclusion Two novel deep intron mutations have been identified in SLC26A4 and SLC5A5, bringing the total number of solved families with disease-causing mutations to approximately 45% in our cohort. Approximately 46% (13/28) of reported noncanonical splice-site mutations do not disrupt pre-mRNA splicing. CADD provides highest prediction accuracy of noncanonical splice-site variants.

Funder

KACST

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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