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.

中文翻译：

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Noonan综合征的严重临床表型与新生儿肥厚性心肌病有关，这是全球第二例RAF1 S259Y新突变的病例。

Noonan综合征和相关疾病是由RAS / MAPK途径的基因突变引起的一组临床和遗传异质性疾病。Noonan综合征会导致多种先天性异常，并经常伴有肥厚性心肌病（HCM）。我们在这里报告了一名突尼斯患者，患有严重的Noonan综合征表型，包括新生儿HCM，面部畸形，重度failure壮衰弱，皮肤异常，眼睑遗骨和严重发育不良，这些患者在生命的第八个月内死亡。使用整个外显子组测序，我们在RAF1基因的第7外显子中发现了一个从头突变：c.776C> A（p.Ser259Tyr）。该突变影响高度保守的丝氨酸残基，丝氨酸残基是通过磷酸化抑制Raf-1的主要介质。据我们所知c.776C> 以前仅在一个产前诊断为Noonan综合征的病例中报道过突变。我们的研究进一步支持了RAF1突变与HCM的惊人相关性，并强调了与RAF1 p.Ser259Tyr突变相关的Noonan综合征的临床严重性。