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

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.

Fig. 1

a Pedigree of the family showing nonconsanguineous union and recessive inheritance pattern. White squares/circles represent unaffected individuals; the black circle represents the affected individual. Diagonal lines indicate deceased individual. Individuals labeled with asterisks were available for the present study. The triangle represents spontaneous abortion (pregnancy not carried to term). b Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears, frontal bossing, and hypermobile and extensible joints. c Polydactyly in the upper limbs. d Complex syndactyly in the lower limbs. e The proband (II-2) revealed a significant decrease in human TTC26 gene expression as compared to the normal control. The bar graph shows the relative expression of TTC26 mRNA, which was determined using qRT-PCR. The results are presented as mean ± standard deviation (n = 2), where (*) signifies a statistically significant difference (p < 0.05) as compared to the control.