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.