Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Majid Alfadhel; Muhammad Umair; Bader Almuzzaini; Abdulaziz Asiri; Abeer Al Tuwaijri; Khaloud Alhamoudi; Yusra Alyafee; Mohammed Al-Owain

doi:10.1159/000513829

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Mol Syndromol. 2021 Jun;12(3):133-140. doi: 10.1159/000513829. Epub 2021 May 11.

Authors

Majid Alfadhel^{1

2

3}, Muhammad Umair^{1

2}, Bader Almuzzaini^{1

2}, Abdulaziz Asiri^{1

4}, Abeer Al Tuwaijri^{1

2}, Khaloud Alhamoudi^{1

2}, Yusra Alyafee^{1

2}, Mohammed Al-Owain⁵

Affiliations

¹ Medical Genomics Research Department, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs (MNGH), Riyadh, Saudi Arabia.
² King Saud Bin Abdulaziz University for Health Sciences, MNGH, Riyadh, Saudi Arabia.
³ Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children's Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
⁴ Faculty of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia.
⁵ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Abstract

Ciliopathies constitute heterogeneous disorders that result from mutations in ciliary proteins. These proteins play an important role in the development of organs, physiology, and signaling pathways, and sequence variations in the genes encoding these proteins are associated with multisystem disorders. In this study, we describe a severe ciliopathy disorder that segregates in an autosomal recessive manner in a nonconsanguineous Saudi family. The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Whole-genome sequencing and Sanger sequencing revealed a homozygous splice site variant (c.4-1G>C; NM_024926.3) in the tetratricopeptide repeat domain 26 (TTC26) gene located in chromosome 7q34, which cosegregated perfectly with the disease phenotype. qRT-PCR revealed a substantial decrease in the expression of the TTC26 gene as compared to the normal control, suggesting the pathogenicity of the identified variant. This report further strengthens the evidence that homozygous variants in the TTC26 gene cause severe ciliopathies with diverse phenotypes. We named this newly characterized condition as BRENS syndrome, which stands for biliary, renal, neurological, and skeletal features.

Keywords: Cholestasis; Ciliopathy; Hydrocephalus; Splice site variant; TTC26.