Discussion and conclusion
Ciliopathy is a genetically heterogeneous group of diseases, which are
caused by an underlying dysfunction of the primary cilium. Skeletal
ciliopathies are the common forms of
ciliopathies,
which can be classified into different subtypes
according
to the clinical manifestations. Besides the common characters of
skeletal development abnormalities, each subtype
has
its own unique feature different from others[12, 24].
As the important subtypes of skeletal ciliopathies, the clinical
manifestations of JATD and SRPS are highly similar. They both manifested
as short ribs, narrow chest, short fingers (toes), with or without
polydactyl[6, 17]. And usually accompanied by the involvement of
extra-skeletal organs such as retinopathy and
fibrocystic
changes in liver and kidney. However, the SRPS phenotype is usually more
severe than JATD, and often leads to
embryonic
developmental disorders and perinatal death, the survival period is
short. while the relative survival rate of JATD is high, about 40%,
could survive to adulthood[13, 15].
In the present report, the proband was an
adult
patient and displayed
modest
phenotype of skeletal abnormalities, such as
a
relatively small thoracic cage,
which
is less conspicuous compared to neonate cases, possibly attributing to
the improvement of respiratory function with age. Whereas, short fingers
(toes) of the extremities are very conspicuous in the patient and
no
other
typical radiological features such as cone-shaped epiphyses can be
distinguished in the patient’s
radiographs,
further illustrating the high variability of JATD manifestations. It is
worth
concerned
that, for this patient, the extra-skeletal
phenotype
- progressive renal failure and retinal degeneration
were
considerably more noticeable than the skeletal changes, which
were
not been concerned until visiting our hospital. So, this case
implied
the crypticity and confusability of JATD phenotype in adult patient.
Notably, the proband’s only sibling died of respiratory failure at
infancy stage without definite diagnosis. It is estimated that 60% of
JATD cases accompanied with lethal respiratory distress after
birth[14]. Once overcome the respiratory dysfunction through a
careful nursing at
early
stage after birth and the survival rate of infants will be improved.
Whereas, 30% of the
survival
JATD patients developed end stage renal disease and 50% of the JATD
cases presented retinal alteration just as the proband in this report,
however, the age of
onset
of extraosseous manifestations are still unevaluated to date[14,
25].
To make a definite diagnosis and find the pathogenic gene, JATD/SRPS
panel including fifteen genes were screened by high-throughput
sequencing, a novel homozygous variant c.2789C>T (p.S930L)
in exon 24 of WDR60 gene was found, and multiple sequences alignment
indicated the evolutionary conservation of the site p.S930L among
different species (figure 4). In silico analysis by four software highly
suggested the variant was a pathogenic form. Current evidence has proved
that WDR60 mutations could cause varying degree phenotypes of JATD or
SRPS[13, 17, 20]. Moreover, one report also confirmed the
destructive effect of WDR60 mutation on cilia structure and assemble by
immunofluorescence in fibroblast derived from affected patient[17].
In our case,
the
patient was in a very serious condition and denied biopsy, so we could
not acquire the
in
vivo evidence of variant disrupting ciliogenesis from this patient. Even
so,
we
have made a point mutation mouse model and we will provide more
intensive investigation on the pathogenic mechanism of
c.2789C>T variant in future study.
In summary, in this report, we identified a novel homozygous variant
c.2789C>T (p.S930L) in a delayed diagnosis of JATD patient.
This report will help to expand our understanding for this disease in
China and enrich the mutational spectrum of WDR60 gene.