A number sign (#) is used with this entry because of evidence that Noonan syndrome-11 (NS11) is caused by heterozygous mutation in the MRAS gene (608435) on chromosome 3q22.

Noonan syndrome-11 (NS11) is characterized by clinical characteristics of Noonan syndrome, varying impairment of intellectual development, and a consistent cardiac phenotype of cardiac hypertrophy (Higgins et al., 2017).

For a phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).

Higgins et al. (2017) reported 2 patients with a clinical diagnosis of Noonan syndrome with concomitant cardiac hypertrophy who were negative for mutations in known Noonan syndrome genes. The first was a 15-year-old girl who presented in infancy with biventricular hypertrophic cardiomyopathy and required surgical myectomy for biventricular outflow tract obstruction at age 8. She had short stature, hypertelorism, and mildly posteriorly rotated ears. She had a static pattern of global developmental delay and cognitive disability. Her parents were unaffected, and there was no family history of Noonan syndrome or related disorders. The second patient was a 6-year-old girl with low-set and posteriorly rotated ears, mild pectus excavatum, wrinkled palms, hyperextensible small joints, ptosis, and hypotonia. In addition, she had cardiac hypertrophy, pulmonary valve stenosis, and atrial septal defect. She had moderate developmental delay, with walking at 2.5 years and first words at age 4, and was not fully toilet trained at 6 years.

Suzuki et al. (2019) reported a 2-year-old boy with Noonan syndrome who was born by forceps delivery at 37 weeks to nonconsanguineous Japanese parents. He presented with cyanosis, tachycardia, and excessive sweating after crying, and was diagnosed with cardiac hypertrophy. His course was complicated by cardiac arrest, necessitating tracheostomy and long-term ventilation. At 4 months of age, he had feeding difficulty and was diagnosed with bilateral sensorineural hearing loss. At 32 months, he could sit alone for brief periods but could not stand. He did not use sign language. At 15 months, his height was -3.0 SD, but OFC was -1.5 SD, demonstrating relative macrocephaly. He had downslanting palpebral fissures, hypertelorism, depressed nasal bridge, bulbous nasal tip, low-set ears with thick lobes, and full lips.

The heterozygous mutations in the MRAS gene that were identified in patients with Noonan syndrome by Higgins et al. (2017) and Suzuki et al. (2019) occurred de novo.

Higgins et al. (2017) reported 2 patients with Noonan syndrome and concomitant cardiac hypertrophy who carried de novo heterozygous missense mutations in the MRAS gene. The first patient carried a gly23-to-val (G23V; 608435.0001) mutation and the second a thr68-to-ile mutation (T68I; 608435.0002). The mutations were identified by whole-exome sequencing and sequencing of the MRAS gene, respectively. The G23V mutation was studied extensively and found to result in a constitutively active form of MRAS.

Suzuki et al. (2019) reported a patient with a severe Noonan phenotype including hypertrophic cardiomyopathy who was heterozygous for a de novo gln71-to-arg (Q71R; 608435.0003) mutation in MRAS. The authors noted that gln71 is highly conserved from zebrafish to humans, and that gln71 of MRAS corresponds to gln61 of HRAS (190020), KRAS (190070), and NRAS (164790), within the nucleotide-binding switch II region critical for the activation of proteins.