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.