Page 35 - Clinical variability in Noonan syndrome with emphasison ear and eye

VARIABLE PHENOTYPIC EXPRESSION IN A LARGE NOONAN SYNDROME FAMILY
Ser2Gly) and in PTPN11 (1226G>C, p.Gly409Ala) was found with symptoms associated with SHOC2 mutations including ectodermal anomalies. They suggest that the PTPN11 mutation might have acted as a modifier, with a less typical phenotype than other NS patients with the SHOC2 mutation (29). Another patient is described with mutations in PTPN11 (c.1121A>G, p.N308S) and SOS1 (c.1654A>G, p.R552G) with typical NS features (28). They conclude that the co-occurring mutations did not have an additive effect and does not lead to a more severe phenotype (28). To exclude co-occurring mutations in this family as an explanation for the phenotypic differences, we tested all NS spectrum genes in the proband and we confirmed solely the SOS1 mutation.
Another hypothesis to explain the large intra-familial variability is described by Moncini (22). They studied three family members with SOS1 mutation, c.755T>C, p.I252T and phenotypical variation. They conducted research on allelic expressions and found different allelic expressions of SOS1 in healthy individuals. They hypothesize that epigenetic mechanisms might be responsible for the variable clinical expression of SOS1 pathogenic alleles. They stated that further studies on epigenetic mechanisms must be performed, to gain more insight in their role in the different allelic expressions in NS (22). Different allelic expression is also studied in general, in the human genome (30). It is suggested that non-coding regions, located in introns and far away from the annotated genes, can be involved in the aetiology of diseases. Further investigation into these regulatory mechanisms in NS patients would be of interest for a better understanding of differences in phenotypic expression.
In this study we describe the different phenotypic expressions in a large NS family due to a new SOS1 mutation. Variety in clinical expressions plays an important role in adequately diagnosing NS patients. Phenotype differs between individuals and between the different generations. Further research is required to understand the detailed pathophysiology.
Acknowledgments
We would like to thank all family members for their participation. The authors have no conflict of interest to disclose.
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