A rare case of Noonan syndrome associated with biallelic variants in the LZTR1

Introduction. Noonan syndrome is a clinically and genetically heterogeneous disease with multiple organ involvement associated with mutations in the genes of the RAS/MAPK signalling pathway. Most patients with Noonan syndrom (up to 50–80%) have disorders of the cardiovascular system, presented by a wide range of congenital heart defects and/or cardiomyopathy, predominantly hypertrophic phenotype. Thanks to the introduction of high-throughput sequencing, knowledge of the genetic causes of Noonan syndrome has expanded significantly, so since 2014, the LZTR1 gene (OMIM 601247) has been included in the list of genes responsible for the development of Noonan syndrome. The nucleotide variants of this gene are known to be inherited both in an autosomal dominant and autosomal recessive manner. However, the number of reports describing the clinical and genetic characteristics of patients with LZTR1 gene mutations is scarce in the world scientific literature.

Objective. To describe the clinical features of Noonan syndrome with an autosomal recessive type of inheritance caused by biallelic variants c.1259A>G (p.Q420R) and c.2051T>C (p.I684T) in the LZTR1 gene.

Materials and methods. A detailed analysis of the history data, the results of clinical, laboratory, and instrumental studies, a molecular genetic study using high-throughput sequencing technology and direct Sanger sequencing was carried out. After verifying the biallelic variants in the proband, a search was made for the identified nucleotide substitutions in the venous blood samples of the parents and sibs.

Results. The article presents the data of a clinical observation of a rare case of Noonan syndrome caused by pathogenic variants in the LZTR1 gene with an autosomal recessive type of inheritance by the Department of Cardiology of the National Medical Research Center for Children’s Health of the Ministry of Health of Russia.

Conclusion. The diversity of clinical manifestations makes it difficult to diagnose Noonan syndrome based on phenotype alone. The possibility of using high-throughput sequencing improves the quality of diagnostics, contributes to the replenishment of data on new pathogenic variants and the establishment of genotype-phenotypic correlations.

Compliance with ethical standards. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee and was approved by the Ethics. The design of the study was approved by the ethics committee of the National Research Center for Children’s Health of the Russian Ministry of Health.

Contribution:
Gandaeva L.A. — concept, editing;
Kaverina V.G. — writing text;
Basargina E.N. — editing;
Pushkov A.A. — editing;
Savostyanov K.V. — concept, editing.
All co-authors are responsible for the  integrity of all parts of the manuscript and approval of its final version.

Conflict of interest. The authors declare no conflict of interest.

Acknowledgment. The study had no financial support. All authors are grateful to the patients and their families for their continuous contributions and support of our research. The authors express their gratitude to the director of the National Research Center for Children’s Health, professor A.P. Fisenko for support and technical assistance in the implementation of this work.

Received: June 28, 2023
Accepted: August 30, 2023
Published: October 13, 2023

1. Rauen K.A. Defining RASopathy. Dis. Model. Mech. 2022; 15(2): dmm049344. https://doi.org/10.1242/dmm.049344

2. Tartaglia M., Gelb B.D., Zenker M. Noonan syndrome and clinically related disorders. Best Pract. Res. Clin. Endocrinol. Metab. 2011; 25(1): 161–79. https://doi.org/10.1016/j.beem.2010.09.002

3. Leoni C., Blandino R., Delogu A.B., De Rosa G., Onesimo R., Verusio V., et al. Genotype-cardiac phenotype correlations in a large single-center cohort of patients affected by RASopathies: Clinical implications and literature review. Am. J. Med. Genet. A. 2022; 188(2): 431–45. https://doi.org/10.1002/ajmg.a.62529

4. Stevenson D.A., Yang F.C. The musculoskeletal phenotype of the RASopathies. Am. J. Med. Genet. C Semin. Med. Genet. 2011; 157(2): 90–103. https://doi.org/10.1002/ajmg.c.30296

5. Romano A.A., Allanson J.E., Dahlgren J., Gelb B.D., Hall B., Pierpont M.E., et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010; 126(4): 746–59. https://doi.org/10.1542/peds.2009-3207

6. Calcagni G., Limongelli G., D’Ambrosio A., Gesualdo F., Digilio M.C., Baban A., et al. Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results. Int. J. Cardiol. 2017; 245: 92–8. https://doi.org/10.1016/j.ijcard.2017.07.068

7. Lioncino M., Monda E., Verrillo F., Moscarella E., Calcagni G., Drago F., et al. Hypertrophic cardiomyopathy in RASopathies: Diagnosis, clinical characteristics, prognostic implications, and management. Heart Fail. Clin. 2022; 18(1): 19–29. https://doi.org/10.1016/j.hfc.2021.07.004

8. Yamamoto G.L., Aguena M., Gos M., Hung C., Pilch J., Fahiminiya S., et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 2015; 52(6): 413–21. https://doi.org/10.1136/jmedgenet-2015-103018

9. Chen P.C., Yin J., Yu H.W., Yuan T., Fernandez M., Yung C.K., et al. Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc. Natl Acad. Sci. USA. 2014; 111(31): 11473–8. https://doi.org/10.1073/pnas.1324128111

10. Chinton J., Huckstadt V., Mucciolo M., Lepri F., Novelli A., Gravina L.P., et al. Providing more evidence on LZTR1 variants in Noonan syndrome patients. Am. J. Med. Genet. A. 2020; 182(2): 409–14. https://doi.org/10.1002/ajmg.a.61445

11. Li X., Yao R., Tan X., Li N., Ding Y., Li J., et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin. Genet. 2019; 96(4): 290–9. https://doi.org/10.1111/cge.13588

12. Pagnamenta A.T., Kaisaki P.J., Bennett F., Burkitt-Wright E., Martin H.C., Ferla M.P., et al. Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome. Clin. Genet. 2019; 95(6): 693–703. https://doi.org/10.1111/cge.13533

13. Johnston J.J., van der Smagt J.J., Rosenfeld J.A., Pagnamenta A.T., Alswaid A., Baker E.H., et al. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet. Med. 2018; 20(10): 1175–85. https://doi.org/10.1038/gim.2017.249

14. El Bouchikhi I., Belhassan K., Moufid F.Z., Iraqui Houssaini M., Bouguenouch L., Samri I., et al. Noonan syndrome-causing genes: molecular update and an assessment of the mutation rate. Int. J. Pediatr. Adolesc. Med. 2016; 3(4): 133–42. https://doi.org/10.1016/j.ijpam.2016.06.003

15. Savostyanov K.V., Namazova-Baranova L.S., Basargina E.N., Vashakmadze N.D., Zhurkova N.V., Pushkov A.A., et al. The new genome variants in Russian children with genetically determined cardiomyopathies revealed with massive parallel sequencing. Vestnik Rossiyskoy akademii meditsinskikh nauk. 2017; 72(4): 242–53. https://doi.org/10.15690/vramn872 https://elibrary.ru/zfourx (in Russian)

16. Tidyman W.E., Rauen K.A. Pathogenetics of the RASopathies. Hum. Mol. Genet. 2016; 25(R2): 123–32. https://doi.org/10.1093/hmg/ddw191

17. Zhang H., Cao X., Wang J., Li Q., Zhao Y., Jin X. LZTR1: A promising adaptor of the CUL3 family. Oncol. Lett. 2021; 22(1): 564. https://doi.org/10.3892/ol.2021.12825

18. Sewduth R.N., Pandolfi S., Steklov M., Sheryazdanova A., Zhao P., Criem N., et al. The Noonan syndrome gene LZTR1 controls cardiovascular function by regulating vesicular trafficking. Circ. Res. 2020; 126(10): 1379–93. https://doi.org/10.1161/circresaha.119.315730

19. Farncombe K.M., Thain E., Barnett-Tapia C., Sadeghian H., Kim R.H. LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis. BMC Med. Genomics. 2022; 15(1): 160. https://doi.org/10.1186/s12920-022-01304-x

20. Chistyakov D.A., Savost’yanov K.V., Turakulov R.I., Shcherbacheva L.N., Mamaeva G.G., Balabolkin M.I., et al. Antioxidant defense genes and predisposition to diabetes. Sakharnyy diabet. 2000; (3): 2–7. https://elibrary.ru/qilnjh (in Russian)

21. Chistiakov D.A., Savost’anov K.V., Turakulov R.I., Petunina N., Balabolkin M.I., Nosikov V.V. Further studies of genetic susceptibility to Graves’ disease in a Russian population. Med. Sci. Monit. 2002; 8(3): CR180-4.

22. Diekmann L., Pfeiffer R.A., Hilgenberg F., Bender F., Reploh H.D. Familial cardiomyopathy with congenital webbed neck. Munch. Med. Wochenschr. 1967; 109(50): 2638-45 (in German)

23. Umeki I., Niihori T., Abe T., Kanno S.I., Okamoto N., Mizuno S., et al. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. Hum. Genet. 2019; 138(1): 21–35. https://doi.org/10.1007/s00439-018-1951-7

24. Perin F., Trujillo-Quintero J.P., Jimenez-Jaimez J., Rodríguez-Vázquez Del Rey M.D.M., Monserrat L., Tercedor L. Two novel cases of autosomal recessive Noonan syndrome associated with LZTR1 variants. Rev. Esp. Cardiol. (Engl. Ed.). 2019; 72(11): 978–80. https://doi.org/10.1016/j.rec.2019.05.002

25. Jenkins J., Barnes A., Birnbaum B., Papagiannis J., Thiffault I., Saunders C.J. LZTR1-related hypertrophic cardiomyopathy without typical Noonan syndrome features. Circ. Genom. Precis. Med. 2020; 13(2): e002690. https://doi.org/10.1161/circgen.119.002690

26. Kaltenecker E., Schleihauf J., Meierhofer C., Shehu N., Mkrtchyan N., Hager A., et al. Long-term outcomes of childhood onset Noonan compared to sarcomere hypertrophic cardiomyopathy. Cardiovasc. Diagn. Ther. 2019; 9(Suppl. 2): S299–309. https://doi.org/10.21037/cdt.2019.05.01

27. Gandaeva L.A., Basargina E.N., Kondakova O.B., Savost’yanov K.V. Surgical treatment of obstructive hypertrophic cardiomyopathy in children with Noonan syndrome. Rossiyskiy pediatricheskiy zhurnal. 2022; 25(2): 96–105. https://doi.org/10.46563/1560-9561-2022-25-2-96-105 https://elibrary.ru/aexzow (in Russian)