Clinical and Molecular Findings of Tunisian Patients with RASopathies

Louati, Rim; Abdelmoula, Nouha Bouayed; Trabelsi, Imen; Abid, Dorra; Lißewski, Christina; Kharrat, Najla; Kamoun, S.; Zenker, Martin; Rebaï, Tarek

doi:10.1159/000362898

Cited by 3 publications

(4 citation statements)

References 35 publications

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“…We did not detect any pathogenic variants in the C terminal region, which is consistent with most other studies [17].…”

Section: Genotype-phenotype Correlationsupporting

confidence: 93%

“…Our cohort had CHD (in 84% of patients with pathogenic variants) mainly consisting of right-sided cardiac anomalies [57]. Studies by Zenker [11], Tartaglia [66], Louati [17] and Ferrero [28] also reported high frequency of CHD. The most frequently occurring pathogenic variants in our cohort, c.922A > G and c.923A > G, both of which change the same amino acid (Asn308), were seen in 22 patients, including a three-generationaffected pedigree.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 61%

“…This may be because the majority of patients were young children seen before pubertal growth had been completed [64]. Characterization of facial features can vary as this is still based on subjective assessment [17]. The most commonly observed facial features in our study were downward slanting palpebral fissures followed by lowset posteriorly rotated ears.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 85%

“…Clinical features such as pulmonary stenosis (PS), short stature and thoracic deformities are more consistently associated with PTPN11 mutations than other clinical features [10][11][12][13][14]. The association of congenital heart defects in some studies is greater than 80% [1,10,11,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] indicating that NS is the second syndrome after Down syndrome with respect to frequency of cardiac defects.…”

Section: Introductionmentioning

confidence: 99%

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Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations

et al. 2020

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Background: Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation. Methods: Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced. Results: Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%). Conclusion: The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.

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“…We did not detect any pathogenic variants in the C terminal region, which is consistent with most other studies [17].…”

Section: Genotype-phenotype Correlationsupporting

confidence: 93%

Section: Genotype-phenotype Correlationmentioning

confidence: 61%

Section: Genotype-phenotype Correlationmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations

et al. 2020

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Noonan syndrome on the African Continent

Tekendo‐Ngongang

Kruszka

2020

Birth Defects Research

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BackgroundNoonan syndrome is a common genetic syndrome caused by pathogenic variants in genes in the Ras/MAPK signaling pathway. The medical literature has an abundance of studies on Noonan syndrome, but few are from the African continent.MethodsThe medical literature was searched for studies on Noonan syndrome from the African continent and these reports were added to our experience in Africa. Facial analysis was reviewed from two previous reports from our group using a support vector machine (SVM) algorithm and an analysis using the Face2Gene convolutional neural network technology.ResultsIndividuals with Noonan syndrome from reports in African populations have the classic phenotype characteristics including typical minor facial anomalies such as widely spaced eyes (31–100%), short stature (71–100%), and congenital heart disease with pulmonary stenosis found in 24–100% of patients. Similarly, the genotypes are similar with the majority of variants occurring in the gene PTPN11 (72%) and 36% of these variants occurred in the amino acid residue Asn308, which is most commonly found in other populations. The two separate facial analysis algorithms successfully discriminated Africans with NS from unaffected matched individuals with area under the curve (AUC) of the receiver operator characteristic of 0.94 (SVM) and 0.979 for the Face2Gene research methodology.ConclusionFew studies characterizing Noonan syndrome in Africans have been conducted, highlighting the need for more genetic and genomic research in African populations. Available clinical data, genotypes, and facial analysis technology data show that individuals of African descent with NS can be efficiently diagnosed using available standards.

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Molecular and environmental characterization of Noonan syndrome in Morocco reveals a significant association with consanguinity and advanced parental age

Bouchikhi

Bouguenouch

Moufid

et al. 2020

Egypt J Med Hum Genet

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Background: Noonan syndrome (NS) is one of the most common RASopathies, with an autosomal dominant inheritance. This disorder is caused by a range of genes belonging to the RAS-MAP kinase (rat sarcoma viral oncogene homolog/mitogen-activated protein kinases) pathway, with PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) being the most involved genetic factor. The aim of this study is to report PTPN11 mutations found in a cohort of Moroccans with Noonan syndrome, compare the mutation rate with various studies, and statistically assess involvement of prominent risk factors in manifestation of this disorder. Thirty-one NS patients were screened for PTPN11 mutations using PCR-Sanger sequencing method. Pathogenic effect prediction, for detected variants, was carried out using PROVEAN, MutationTaster2, and HSF programs. Statistical tests were performed with R software. Chi-square and Fisher's exact tests were used in percentage comparisons, while Student's test was used in average comparisons. Results: We detected five pathogenic mutations, one synonymous variant with a potential altering effect on splicing function, and three novel intronic duplications. PTPN11 mutation rate in our cohort is around 16.13%. Comparison of this rate with the corresponding rates in various populations shows notably significant differences across continents. Conclusions: Besides genetic factors, the present study suggests involvement of additional environmental factors. Statistical assessment of clinical data confirms particularly the association of NS manifestation with consanguinity and advanced paternal age, and suggests an eventual implication of advanced maternal age as well.

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Clinical and Molecular Findings of Tunisian Patients with RASopathies

Cited by 3 publications

References 35 publications

Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations

Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations

Noonan syndrome on the African Continent

Molecular and environmental characterization of Noonan syndrome in Morocco reveals a significant association with consanguinity and advanced parental age

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