Noonan Syndrome (NS) is a genetic condition characterized by congenital heart defects, short stature and characteristic facial features. We analyzed a girl with moderate learning disabilities, delayed language development, craniofacial features and skin anomalies reminiscent of NS. After a mutation screening of the known NS genes PTPN11, SOS1, RAF1, KRAS, GRB2, BRAF and SHOC2 we found the heterozygous c.755T/C variation in SOS1 causing the I252T substitution, which was considered possibly pathogenetic by bioinformatic predictions. The same mutation was present in the proband’s mother and maternal grandfather, both displaying some NS features, but also by a healthy subject on 1000 genomes analyzed. The functional analysis revealed that the SOS1 c.755T/C activated the Ras effector Erk1, confirming the predicted pathogenetic substitution. To explain the incomplete penetrance of the reported mutation we hypothesized that SOS1 may be subjected to a differential allelic expression (DAE). Interestingly, after sequencing the cDNA from peripheral blood compared to genomic DNA, we showed a DAE of some known SOS1 SNSs in healthy individuals and observed the mutated allele C 50% more expressed than the normal allele T in all our NS familial carriers. The similar level of SOS1 mRNA, between mutated and control individuals, suggests that the mutation here described does not affect SOS1 expression. We are now evaluating the SOS1 promoter polymorphisms. This study, providing the first evidence of allelic imbalance of SOS1, pinpoint DAE as a possible mechanism underlying a different penetrance of some SOS1 mutated alleles in unrelated carriers.

Differential allelic expression of the SOS1 c.755C activating variant in a Noonan syndrome family / S. Moncini, M. T. Bonati, I. Morella, L. Ferrari, R. Brambilla, P. Riva. - In: EUROPEAN JOURNAL OF HUMAN GENETICS. - ISSN 1018-4813. - 22:suppl. 1(2014 May), pp. 270-270. ((Intervento presentato al convegno European Human Genetics Conference in conjunction with European Meeting on Psychosocial aspects of Genetics tenutosi a Milano nel 2014 [10.1038/ejhg.2013.133].

Differential allelic expression of the SOS1 c.755C activating variant in a Noonan syndrome family

S. Moncini;L. Ferrari;P. Riva
2014-05

Abstract

Noonan Syndrome (NS) is a genetic condition characterized by congenital heart defects, short stature and characteristic facial features. We analyzed a girl with moderate learning disabilities, delayed language development, craniofacial features and skin anomalies reminiscent of NS. After a mutation screening of the known NS genes PTPN11, SOS1, RAF1, KRAS, GRB2, BRAF and SHOC2 we found the heterozygous c.755T/C variation in SOS1 causing the I252T substitution, which was considered possibly pathogenetic by bioinformatic predictions. The same mutation was present in the proband’s mother and maternal grandfather, both displaying some NS features, but also by a healthy subject on 1000 genomes analyzed. The functional analysis revealed that the SOS1 c.755T/C activated the Ras effector Erk1, confirming the predicted pathogenetic substitution. To explain the incomplete penetrance of the reported mutation we hypothesized that SOS1 may be subjected to a differential allelic expression (DAE). Interestingly, after sequencing the cDNA from peripheral blood compared to genomic DNA, we showed a DAE of some known SOS1 SNSs in healthy individuals and observed the mutated allele C 50% more expressed than the normal allele T in all our NS familial carriers. The similar level of SOS1 mRNA, between mutated and control individuals, suggests that the mutation here described does not affect SOS1 expression. We are now evaluating the SOS1 promoter polymorphisms. This study, providing the first evidence of allelic imbalance of SOS1, pinpoint DAE as a possible mechanism underlying a different penetrance of some SOS1 mutated alleles in unrelated carriers.
Settore BIO/13 - Biologia Applicata
European Society of Human Genetics
https://www.eshg.org/fileadmin/www.eshg.org/conferences/2014/ESHG2014Abstracts.pdf
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/243946
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