Syndromic ciliopathy: a taiwanese single-center study

Abstract

Background: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.

Methods: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.

Results: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.

Conclusions: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.

Keywords: Alström syndrome; Bardet-biedl syndrome; Ciliopathy; Joubert syndrome; Oral-facial-digital syndrome; Whole exome sequencing.

Fig. 1

Pairwise kinship coefficients were calculated using VCFTOOLS relatedness2 function to determine the relatedness between each pair of cases in our cohort, which included two Taiwanese patients with a disorder of sex development (DSD) and one Caucasian with Noonan syndrome (NS) serving as controls. P6 and P7 were excluded from the analysis since they are siblings. The kinship values ranged from the lowest at 0.043826 to the highest at 0.127509. The Caucasian with Noonan syndrome was the most unrelated individual to the other cases, while the Taiwanese individuals, regardless of having ciliopathy or DSD, exhibited similar kinship values, reflecting the genetic background of the Taiwanese population

Fig. 2

(A) ALMS1 protein and the truncated mutations of P10 and P11 on ALMS1 gene (B) OFD1 protein and the truncated mutation of P13 on OFD1 gene

Fig. 3

C2CD3 (C2 calcium-dependent domain containing 3) protein has six canonical PKC-C2 domains and a C2CD3N–C2 domain at the N-terminus [25]. The graph showed the conserved amino acid residues at the 577 and 907 positions on C2CD3 protein (A). The iterative threading assembly refinement (I-TASSER) server was used to predict the three-dimensional structure of wild type (B and D) and mutant (C and E) C2CD3 protein. The yellow dashed line indicates the hydrogen bond. (C) The H577 residue is predicted to form a new hydrogen bond with V623 residue, which slightly changed the β-sheet structure. (E) The C907 residue is predicted to cause hydrogen bond loss with H904 and F910 and form a new hydrogen bond with the S909 residue, affecting the proper protein folding in the α‐helix