Case presentation
The proband was a 46 -year-old male patient from healthy consanguineous parents. At about 38 years old, he was admitted to local hospital for dizziness. Examination and laboratory data on admission showed the blood pressure was 200mmHg/110mmHg, Serum Cr (1200μmol/L), respectively. The diagnoses of hypertension and chronic kidney disease (stage 5) were made according to his clinical features and biochemical data at that time. Then an antihypertensive therapy was taken by administration of antihypertensive drugs to control the blood pressure within normal range (about 140-150 mmHg/90 mmHg), and regular hemodialysis was adopted to improve the survival status and prognosis. 1 year ago, he was hospitalized to our hospital because of dizziness, headache and alalia, brain CT demonstrated hemorrhage in his left brain. Notably, physical examination on admission in our hospital showed the patient displayed disproportional short stature, with normal height (170cm), while presented conspicuous small chest and short extremities with brachydactyly and accompanied with deformity teeth (Figure 1). In addition, the routine fundoscopy revealed the concurrent existence of bilateral retinitis pigmentosa in this patient (Figure 2). According to the above-mentioned clinical characters and the history of kidney failure, the patient was reassessment and suggested the diagnosis of JATD. Clinical features and representative biochemical data are shown in table 1. The pedigree tree was shown in figure 3.
To confirm the diagnosis, genetic analysis was performed after the patient and his family members gave informed consent. The study protocol was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University. Genomic DNA was extracted from the peripheral blood leucocytes using Blood genome DNA Extraction kit (Promega, USA). High-throughput sequencing was used to analyze all the exon regions and adjacent intronic regions of JATD/SRPS associated genes that have been reported previously including CEP120, DYNC2H1, EVC, EVC2, IFT43, IFT80, IFT122, IFT140, IFT172, NEK1, TTC21B, WDR19, WDR34, WDR35, and WDR60[14, 15, 17, 21, 22, 23]. After raw data processing, reads that passed were then mapped to the human reference genome (UCSC hg19) using the Burrows Wheeler Aligner (University of California, Santa Cruz, CA, USA). The variant call file (VCF) containing the detected variants was annotated with Variant Effect Predictor v83 and the dbNSFP (Database for Nonsynonymous SNPs’ Functional Predictions) v3.1. After the selection process, a novel homozygous variant c.2789C>T (p.S930L) in exon 24 of WDR60 gene was found in the proband and the heterozygous variant was detected in his parents and his daughter. The variant was then confirmed by sanger sequencing verification (Figure 4). No mutation was found in any other pathogenic genes and no c.2789C>T (p.S930L) variant was found in one-hundred unrelated healthy subjects. According to guidelines from the American College of Medical Genetics and Genomics (ACMG, 2015), the variant was preliminarily determined as pathogenic (PM2 + PP3). PM2: the frequency in normal population database is 0.0003, which is low-frequency variation; PP3: protein function predicted as harmful, benign, harmful and harmful, by prediction software SIFT, polyphen-2, Mutationtaster and GERP + +, respectively.