Abstract
Cockayne syndrome is a rare condition that encompasses a very wide spectrum of clinical severity. Mutations upstream of a transposon called PiggyBac Transposable Element Derived 3 in intron 5 of the CSB/ERCC6 gene could bring about less severe forms than mutations located downstream of that transposon insertion. Our aim was to study genotype-phenotype correlation by determining whether the position of each mutation of the CSB/ERCC6 gene has an impact on the phenotype. A hundred and forty-seven Cockayne patients, who had two pathogenic mutations in the CSB/ERCC6 gene and for whom clinical data was available, were retrospectively selected and included in the study. Data analysis was performed under the Bayesian paradigm. Analysis of the proportion of the different subtypes of Cockayne syndrome according to the position of the mutations was done using an ordinal logistic regression model. Using a vague prior, the risk of developing a more severe subtype when exposed to 2 mutations downstream compared to 2 mutations upstream was 2.0 [0.9–4.5]. Estimations varied through the sensitivity analysis. We could reasonably conclude that a relationship between the number of downstream mutations and the Cockayne syndrome clinical expression exists but it is still difficult to give a precise estimate of this relationship. The real effect could be more complex that the one described in the initial model and other genetic factors might be taken into consideration together with the mutation site to better explain clinical variability.
Highlights
Cockayne syndrome (CS) is an autosomal recessive disorder characterized by growth failure, developmental delay, microcephaly, sensorial alteration, cutaneous photosensitivity, dental anomalies and a recognizable facial appearance (Cockayne, 1946)
A total of 147 patients were included in the study, of whom 24 (16.3%) had 2 mutations upstream of PiggyBac (2U) of PiggyBac, 18 (12.2%) had 1U1D of PiggyBac and 105 (71.4%) had 2 mutations downstream of PiggyBac (2D) of PiggyBac (Table 1)
Accumulating clinical data shows that Cockayne syndrome is a continuous spectrum of forms of varying severity (Laugel, 2013) and no study has brought to light a clear-cut genotype-phenotype correlation so far
Summary
Cockayne syndrome (CS) is an autosomal recessive disorder characterized by growth failure, developmental delay, microcephaly, sensorial alteration, cutaneous photosensitivity, dental anomalies and a recognizable facial appearance (Cockayne, 1946). Several stages of severity have been described previously They essentially depend on the age at first symptoms and on how quickly the disease develops (Natale, 2011; Laugel, 2013). In the classical form or CS type I, symptoms usually start at the end of the first year or in the second year of life. All the symptoms mentioned above can show up progressively This type leads to premature death mainly in the second decade of life. CS type II is equivalent to severe congenital forms. Cerebro-oculo-facio-skeletal (COFS) syndrome is described as an arthrogryposis (Graham et al, 2001). It starts before birth and is associated with a major handicap and death within the first years of life
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