Clinical and Genetic Characterization of Noonan Syndrome in a Romanian Cohort from Transylvania: Details on PTPN11 c.922A>G Variant and Phenotypic Spectrum

Nazarie, Florina Victoria; Miclea, Diana; Șufană, Crina; Botezatu, Alina; Popp, Radu Anghel; Pascanu, Ionela Maria; Alkhzouz, Camelia; Bucerzan, Simona; Lazăr, Călin; Lazea, Cecilia; Vulturar, Romana

doi:10.3390/diagnostics15212753

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Clinical and Genetic Characterization of Noonan Syndrome in a Romanian Cohort from Transylvania: Details on PTPN11 c.922A>G Variant and Phenotypic Spectrum

by

Florina Victoria Nazarie

¹

,

Diana Miclea

^2,3,*

,

Crina Șufană

⁴,

Alina Botezatu

⁵

,

Radu Anghel Popp

¹

,

Ionela Maria Pascanu

⁶

,

Camelia Alkhzouz

^2,3

,

Simona Bucerzan

^2,3

,

Călin Lazăr

^2,4

,

Cecilia Lazea

^2,4,†

and

Romana Vulturar

^7,†

¹

Discipline of Medical Genetics, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, 6, Pasteur St, 400349 Cluj-Napoca, Romania

²

1st Pediatric Discipline, Mother and Child Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, 68, Calea Moților St, 400370 Cluj-Napoca, Romania

³

Medical Genetics Compartment, Children’s Emergency Clinical Hospital, 400370 Cluj-Napoca, Romania

⁴

1st Pediatrics Clinic, Children’s Emergency Clinical Hospital, 68, Calea Moților St, 400370 Cluj-Napoca, Romania

⁵

Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 34, Victor Babes St, 400012 Cluj-Napoca, Romania

⁶

Department of Endocrinology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, 46, Gheorghe Marinescu St, 540136 Târgu Mureș, Romania

⁷

Discipline of Cell and Molecular Biology, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 6, Pasteur St, 400349 Cluj-Napoca, Romania

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Diagnostics 2025, 15(21), 2753; https://doi.org/10.3390/diagnostics15212753

Submission received: 26 August 2025 / Revised: 11 October 2025 / Accepted: 27 October 2025 / Published: 30 October 2025

(This article belongs to the Special Issue Insights into Pediatric Genetics)

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Abstract

Background: Noonan syndrome (NS) is a genetically heterogeneous condition within the RASopathies spectrum, with distinctive craniofacial features, congenital heart defects, short stature, and variably present developmental delay. Most cases result from variants in genes regulating the RAS/MAPK pathway, with PTPN11 variants being the most frequent; the c.922A>G substitution being among the most commonly reported. Methods: This pilot study analyzed clinical and partial genetic features of NS in a cohort from Transylvania, evaluated in the Children’s Emergency Clinical Hospital in Cluj-Napoca. Thirty-one patients fulfilling the Van der Burgt diagnostic criteria (twenty-two males, nine females) were included. Clinical data were systematically reviewed, and targeted molecular testing for the PTPN11 c.922A>G variant was performed. Results: Congenital heart defects were highly prevalent, with pulmonary stenosis representing the most frequent anomaly (54.8%). Craniofacial dysmorphism was observed in 76.7% of cases, cryptorchidism in 50% of the males, and short stature below the third percentile was described in 77.4% of patients. Genetic screening identified the PTPN11 c.922A>G variant in two individuals (6.45%). Additional diagnoses included Williams–Beuren syndrome and a 17q11.2 deletion consistent with Neurofibromatosis–Noonan syndrome, underscoring the clinical and genetic heterogeneity of the cohort. Comparison with international reports highlighted variability in phenotype and variant frequency. Future research directions include Sanger sequencing of key PTPN11 exons and the application of next-generation sequencing targeting all RAS pathway genes. Conclusions: This is the first Romanian cohort study on patients with a clinical suspicion of NS, providing insight into their evaluation. The findings reinforce the need for comprehensive molecular approaches, facilitating diagnostic precision and counseling strategies.

Keywords: Noonan syndrome; RAS/MAPK pathway; RASopathies; PTPN11 c.922A>; G (p.Asn308Asp); pulmonary valve stenosis; Williams–Beuren syndrome; neurofibromatosis–Noonan syndrome

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MDPI and ACS Style

Nazarie, F.V.; Miclea, D.; Șufană, C.; Botezatu, A.; Popp, R.A.; Pascanu, I.M.; Alkhzouz, C.; Bucerzan, S.; Lazăr, C.; Lazea, C.; et al. Clinical and Genetic Characterization of Noonan Syndrome in a Romanian Cohort from Transylvania: Details on PTPN11 c.922A>G Variant and Phenotypic Spectrum. Diagnostics 2025, 15, 2753. https://doi.org/10.3390/diagnostics15212753

AMA Style

Nazarie FV, Miclea D, Șufană C, Botezatu A, Popp RA, Pascanu IM, Alkhzouz C, Bucerzan S, Lazăr C, Lazea C, et al. Clinical and Genetic Characterization of Noonan Syndrome in a Romanian Cohort from Transylvania: Details on PTPN11 c.922A>G Variant and Phenotypic Spectrum. Diagnostics. 2025; 15(21):2753. https://doi.org/10.3390/diagnostics15212753

Chicago/Turabian Style

Nazarie, Florina Victoria, Diana Miclea, Crina Șufană, Alina Botezatu, Radu Anghel Popp, Ionela Maria Pascanu, Camelia Alkhzouz, Simona Bucerzan, Călin Lazăr, Cecilia Lazea, and et al. 2025. "Clinical and Genetic Characterization of Noonan Syndrome in a Romanian Cohort from Transylvania: Details on PTPN11 c.922A>G Variant and Phenotypic Spectrum" Diagnostics 15, no. 21: 2753. https://doi.org/10.3390/diagnostics15212753

APA Style

Nazarie, F. V., Miclea, D., Șufană, C., Botezatu, A., Popp, R. A., Pascanu, I. M., Alkhzouz, C., Bucerzan, S., Lazăr, C., Lazea, C., & Vulturar, R. (2025). Clinical and Genetic Characterization of Noonan Syndrome in a Romanian Cohort from Transylvania: Details on PTPN11 c.922A>G Variant and Phenotypic Spectrum. Diagnostics, 15(21), 2753. https://doi.org/10.3390/diagnostics15212753

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Clinical and Genetic Characterization of Noonan Syndrome in a Romanian Cohort from Transylvania: Details on PTPN11 c.922A>G Variant and Phenotypic Spectrum

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