ORPHA: 648; DO: 0112170;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.2 | Noonan syndrome 12 | 618624 | Autosomal dominant | 3 | RRAS2 | 600098 |
A number sign (#) is used with this entry because of evidence that Noonan syndrome-12 (NS12) is caused by heterozygous mutation in the RRAS2 gene (600098) on chromosome 11p15.
Noonan syndrome-12 (NS12) is characterized by macrocephaly and a recognizable facies, including hypertelorism, downslanting palpebral fissures, and low-set ears, as well as other features consistent with a Noonan syndrome diagnosis. Inter- and intrafamilial variability has been observed (Capri et al., 2019; Niihori et al., 2019).
For a general phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).
Capri et al. (2019) reported 9 patients from 6 families with Noonan syndrome and mutations in the RRAS2 gene. Most patients exhibited the characteristic facial gestalt, although it was less apparent in adulthood. There was considerable variability in severity, with some members of 1 family (family 3) having relatively mild disease whereas another patient (subject 4) died at 2 weeks of life with severe failure to thrive. The authors noted that 5 of the 6 probands exhibited prenatal features, including nuchal edema and/or polyhydramnios, but none had pulmonary valve stenosis or hypertrophic cardiomyopathy.
The heterozygous mutations in the RRAS2 gene that were identified in 6 families with Noonan syndrome by Capri et al. (2019) occurred de novo in 5 families; in 1 family (family 3), the mutation segregated in 4 similarly affected relatives.
In 9 patients from 6 families with Noonan syndrome, Capri et al. (2019) identified heterozygous mutations in the RRAS2 gene (see, e.g., 600098.0001-600098.0003), which segregated with disease in 1 family (family 3) and arose de novo in the probands from the remaining 5 families. The mutations were identified by whole-exome sequencing (WES) and confirmed by Sanger sequencing.
Niihori et al. (2019) performed WES in 27 patients with clinically diagnosed or suspected Noonan syndrome (NS) or NS-related disorder, without known RASopathy mutations, and identified 2 girls (NS462 and NS833) who were heterozygous for de novo mutations in the RRAS2 gene (see, e.g., 600098.0003). Subsequent sequencing of RRAS2 in 191 additional patients suspected of having NS or NS-related disorders did not reveal any additional pathogenic variants. They also performed WES in a boy (HU1) who died at age 3 years with severe failure to thrive, and identified heterozygosity for the Q72L substitution (600098.0001); retrospective inspection of images from infancy showed the facial gestalt of NS. All 3 mutation-positive individuals exhibited macrocephaly and typical or suggestive facial appearance of NS as well as clinical manifestations sufficient to fulfill diagnostic criteria, although the features were not common among all of them.
Capri, Y., Flex, E., Krumbach, O. H. F., Carpentieri, G., Cecchetti, S., Lissewski, C., Adariani, S. R., Schanze, D., Brinkmann, J., Piard, J., Pantaleoni, F., Lepri, F. R., and 21 others. Activating mutations of RRAS2 are a rare cause of Noonan syndrome. Am. J. Hum. Genet. 104: 1223-1232, 2019. [PubMed: 31130282] [Full Text: https://doi.org/10.1016/j.ajhg.2019.04.013]
Niihori, T., Nagai, K., Fujita, A., Ohashi, H., Okamoto, N., Okada, S., Harada, A., Kihara, H., Arbogast, T., Funayama, R., Shirota, M., Nakayama, K., Abe, T., Inoue, S., Tsai, I.-C., Matsumoto, N., Davis, E. E., Katsanis, N., Aoki, Y. Germline-activating RRAS2 mutations cause Noonan syndrome. Am. J. Hum. Genet. 104: 1233-1240, 2019. [PubMed: 31130285] [Full Text: https://doi.org/10.1016/j.ajhg.2019.04.014]