ORPHA: 648; DO: 0060588;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q11.21 | Noonan syndrome 10 | 616564 | Autosomal dominant | 3 | LZTR1 | 600574 |
A number sign (#) is used with this entry because of evidence that Noonan syndrome-10 (NS10) is caused by heterozygous mutation in the LZTR1 gene (600574) on chromosome 22q11.
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 unrelated families with Noonan syndrome-10. The patients had typical facial features, including downslanting palpebral fissures, hypertelorism, ptosis, and short neck, and cardiac abnormalities, mainly pulmonary stenosis and mitral valve defects. Less common features included short stature, pectus deformities, ectodermal involvement, coagulation abnormalities, and cognitive disabilities. One patient developed multiple schwannomas on the arm.
Umeki et al. (2019) reported 6 patients with NS10. All had cardiac defects including 4 with hypertrophic cardiomyopathy and 3 with atrial septal defect. Five had intellectual disability and 4 had short stature.
The transmission pattern of Noonan syndrome-10 in the families reported by Yamamoto et al. (2015) was consistent with autosomal dominant inheritance.
In affected members of 5 families with Noonan syndrome-10, Yamamoto et al. (2015) identified 5 different heterozygous missense mutations in the LZTR1 gene (see, e.g., 600574.0007-600574.0009). All of the mutations occurred in the Kelch (KT) domains, but functional studies of the variants were not performed. Mutations in 4 of the families were found by whole-exome sequencing of a cohort of 50 Brazilian patients with Noonan syndrome; the fifth family was of Polish origin.
Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. Hum. Genet. 138: 21-35, 2019. [PubMed: 30368668] [Full Text: https://doi.org/10.1007/s00439-018-1951-7]
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]