Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

Chronic kidney disease (CKD) remains one of the major common health problems, and the number of people affected by the disease is progressively increasing in Turkey and worldwide. This study aimed to investigate molecular defects in Alport syndrome (AS) and other genes in patients with clinically suspected CKD using whole-exome sequencing (WES). Patients with clinical suspicion of CKD were included in the study. Molecular genetic analyses were performed on genomic DNA by using WES. A total of 15 with 5 different pathogenic or likely pathogenic variants were identified in CKD patients, with a diagnostic rate of 30%. Eight variants of uncertain significance were also detected. In this study, 10 variants were described for the first time. As a result, we detected variants associated with CKD in our study population and found AS as the most common CKD after other related kidney diseases. Our results suggest that in heterogeneous diseases such as CKD, WES analysis enables accurate identification of underlying molecular defects promptly. Although CKD accounts for 10–14% of all renal dysfunction, molecular genetic diagnosis is necessary for optimal long-term treatment, prognosis, and effective genetic counseling.

Introduction: Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers an useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in USP53 have recently been reported in cholestasis phenotype. Methods: In this study, we aimed to characterize clinical findings and biological insights on a novel USP53 splice variant causing cholestasis phenotype and provided a review of the literature. We performed whole-exome sequencing and then confirmed it with Sanger sequencing. In addition, as a result of in silico analyses and cDNA analysis, we showed that the USP53 protein in our patient was shortened. Results: We report a novel splice variant (NM_019050.2:c.238–1G>C) in the USP53 gene via whole-exome sequencing in a patient with cholestasis phenotype. This variant was confirmed by Sanger sequencing and was a result of family segregation analysis; it was found to be in a heterozygous state in the parents and the other healthy elder brother of our patient. According to in silico analyses, the change in the splice region resulted in an increase in the length of exon 2, whereas the stop codon after the additional 3 amino acids (VTF) caused the protein to terminate prematurely. Thus, the mature USP53 protein, consisting of 1,073 amino acids, has been reduced to a small protein of 82 amino acids. Conclusion: We propose a model for the tertiary structure of USP53 for the first time, and together with all these data, we support the association of biallelic variants of the USP53 gene with cholestasis phenotype. We also present a comparison of previously reported patients with USP53-associated cholestasis phenotype to contribute to the literature.