Abstract
Noonan syndrome (NS) is an autosomal-dominant disorder with variable expressivity and locus heterogeneity. Despite several RAS pathway genes were implicated in NS, 20–30% of patients remain without molecular diagnosis, suggesting the involvement of further genes or multiple mechanisms. Eight patients out of 60, negative for conventional NS mutation analysis, with heterogeneous NS phenotype were investigated by means of target resequencing of 26 RAS/MAPK pathway genes. A trio was further characterized by means of whole-exome sequencing. Protein modeling and in silico prediction of protein stability allowed to identify possible pathogenic RAS pathway variants in four NS patients. A new c.355T>C variant in LZTR1 was found in patient 43. Two patients co-inherited variants in LRP1 and LZTR1 (patient 53), or LRP1 and SOS1 genes (patient 67). The forth patient (56) carried a compound heterozygote of RASAL3 gene variants and also an A2ML1 variant. While these subclinical variants are singularly present in healthy parents, they co-segregate in patients, suggesting their addictive effect and supporting a digenic inheritance, as alternative model to a more common monogenic transmission. The ERK1/2 and SAPK/JNK activation state, assessed on immortalized lymphocytes from patients 53 and 67 showed highest phosphorylation levels compared to their asymptomatic parents. These findings together with the lack of their co-occurrence in the 1000Genomes database strengthen the hypothesis of digenic inheritance in a subset of NS patients. This study suggests caution in the exclusion of subclinical variants that might play a pathogenic role providing new insights for alternative hereditary mechanisms.
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Acknowledgements
The authors wish to thank: Marinella Volontè (Dipartimento di Biotecnologie Mediche e Medicina Traslazionale—Università degli Studi di Milano) for her technical support, Nadia Barizzone for her statistical consulence, the families involved in the study and the “Biobank of the Laboratory of Human Genetics”, member of the Telethon Network of Genetic Biobanks (project no. GTB18001), funded by Telethon Italy, and of the EuroBioBank network, provided us with specimens”.
Funding
The study was supported by Academic funding to PR (University of Milan) and by the Ministry of Health ‘Ricerca Corrente’, Grant number 08C607_2006, to IRCCS Istituto Auxologico Italiano.
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Ferrari, L., Mangano, E., Bonati, M.T. et al. Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model?. Eur J Hum Genet 28, 1432–1445 (2020). https://doi.org/10.1038/s41431-020-0658-0
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DOI: https://doi.org/10.1038/s41431-020-0658-0
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