Page 34 - Clinical variability in Noonan syndrome with emphasison ear and eye

CHAPTER 2
Mutation analysis
Sequencing of the SOS1 gene revealed a heterozygous transversion from cytosine to guanine at nucleotide position c.3134C>G leading to a missense mutation p.Pro1045Arg. This mutation has not been reported before in literature or in the ExAC database (24). However, the index person and one family member carrying this mutation are included in an earlier study reporting NS and hearing impairment (25). The amino acid change affects an evolutionarily moderately conserved Proline changing it to an Arginine at position 1045. The detected p.Pro1045Arg change was detected heterozygously in all 10 tested and clinically affected family members with permission for genetic testing. No pathogenic mutations or variants of uncertain significance are detected in the other sixteen tested NS / RASopathy genes in the index case.
Discussion
In this study we describe a new SOS1 mutation, segregated in a large NS family with 10 genetically confirmed affected individuals. In the proband (individual IV-8) with clinically definitive NS, all NS genes are tested and solely this SOS1 mutation is found. There is a broad phenotypic range from almost no NS characteristics to typical phenotypic presentation of NS. These findings and the absence in control individuals support the pathogenetic role of the SOS1, c.3134C>G, p.Pro1045Arg mutation. Genotype-phenotype studies show large inter- and intra-familial variability in clinical features of NS due to the different mutations in the different NS genes (21,26).
From ten family members with the SOS1 mutation, three have suggestive facial characteristics for NS (all of them in generation III) and two have a typical NS face (both in generation IV). A change in facial phenotype with age is described often in NS. These changes may be due to genetic heterogeneity, but can also be caused by changing facial characteristics with age (27).
The facial photographs of 21 individuals with SOS1 mutations from infancy to adulthood are described in literature (21). They describe a high prevalence of coarseness of facial features and ptosis. At adult age, characteristic appearance of NS may be present but affected individuals can also have unremarkable faces (21). We have not performed a photograph study from infancy to childhood, but we find similar characteristics: sparse hair and eyebrows in three and ptosis in seven affected family members at adult age.
In previous research is has been suggested that co-occurring mutations in NS can lead to different phenotypes (28,29). In one patient both a mutation in SHOC2 (c.4A>G, p.
32