Jaouadi Hager, Chehida Amel Ben, Kraoua Lilia, Etchevers Heather C, Argiro Laurent, Kasdallah Nadia, Blibech Sonia, Delague Valérie, Lévy Nicolas, Tebib Néji, Mrad Ridha, Abdelhak Sonia, Benkhalifa Rym, Zaffran Stéphane
Biomedical Genomics and Oncogenetics Laboratory LR16IPT05,Institut Pasteur de Tunis,Université Tunis El Manar,Tunis,Tunisia.
Department of Pediatrics and Metabolic Diseases,La Rabta Hospital,Faculty of Medicine of Tunis,University of Tunis El Manar,Tunis,Tunisia.
Genet Res (Camb). 2019 Apr 29;101:e6. doi: 10.1017/S0016672319000041.
Noonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C > A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C > A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation.
努南综合征及相关疾病是一组临床和遗传异质性疾病，由RAS/MAPK信号通路基因的突变引起。努南综合征会导致多种先天性异常，常伴有肥厚型心肌病（HCM）。我们在此报告一名突尼斯患者，其患有努南综合征的严重表型，包括新生儿肥厚型心肌病、面部畸形、严重发育不良、皮肤异常、漏斗胸和严重生长发育迟缓，该患者在其生命的第八个月死亡。通过全外显子组测序，我们在RAF1基因的第7外显子中鉴定出一个新发突变：c.776C＞A（p.Ser259Tyr）。该突变影响一个高度保守的丝氨酸残基，这是通过磷酸化抑制Raf-1的主要介质。据我们所知，c.776C＞A突变此前仅在一例产前诊断为努南综合征的病例中被报道过。我们的研究进一步支持了RAF1突变与肥厚型心肌病之间的显著相关性，并突出了与RAF1 p.Ser259Tyr突变相关的努南综合征的临床严重性。
