ORPHA: 648; DO: 0060587;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q21.3 | Noonan syndrome 9 | 616559 | Autosomal dominant | 3 | SOS2 | 601247 |
A number sign (#) is used with this entry because of evidence that Noonan syndrome-9 (NS9) is caused by heterozygous mutation in the SOS2 gene (601247) on chromosome 14q21.
Noonan syndrome is an autosomal dominant disorder characterized by short stature, craniofacial dysmorphism, short and/or webbed neck, cardiac abnormalities, cryptorchidism, and coagulation defects (summary by Yamamoto et al., 2015).
For a phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).
Yamamoto et al. (2015) reported 5 patients from 3 unrelated families with Noonan syndrome-9. Two of the families were of Brazilian origin. The patients had mild short stature, webbed neck, and typical dysmorphic facial features, including downslanting palpebral fissures, hypertelorism, and ptosis. Three patients had cardiac defects, including septal defects, coarctation of the aorta, and pulmonary valve stenosis. Ectodermal abnormalities were also noted in most patients, including curly hair, sparse eyebrows, hyperkeratosis pilaris, and ulerythema ophryogenes. Three patients had developmental delay and/or learning disabilities, and 2 had coagulation defects. None of the patients had tumors.
The transmission pattern of Noonan syndrome-9 in the families reported by Yamamoto et al. (2015) was consistent with autosomal dominant inheritance.
In a Brazilian mother and daughter with Noonan syndrome-9, Yamamoto et al. (2015) identified a heterozygous missense mutation in the SOS2 gene (T376S; 601247.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. A different de novo heterozygous missense mutation (M267K; 601247.0002) was identified in a Brazilian patient with sporadic occurrence of the disorder. The 2 probands were from a cohort of 50 Brazilian patients with Noonan syndrome who underwent whole-exome sequencing and thus accounted for 4% of patients in this cohort. However, there was no statistical difference between the frequency of SOS2 variants identified in the patients (2 of 50) compared to variants identified in controls (3 of 107). The T376S mutation was subsequently found in a mother and daughter with Noonan syndrome from the United States. Functional studies of the variants were not performed. Yamamoto et al. (2015) hypothesized that mutations in SOS2 cause Noonan syndrome through a mechanism similar to that of SOS1 (182530), which causes NS4 (610733): a gain of function resulting in enhanced signaling and upregulation of the RAS/MAPK pathway.
Yamamoto, G. L., Aguena, M., Gos, M., Hung, C., Pilch, J., Fahiminiya, S., Abramowicz, A., Cristian, I., Buscarilli, M., Naslavsky, M. S., Malaquias, A. C., Zatz, M., Bodamer, O., Majewski, J., Jorge, A. A. L., Pereira, A. C., Kim, C. A., Passos-Bueno, M. R., Bertola, D. R. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 52: 413-421, 2015. [PubMed: 25795793] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103018]