Dataset Information

Clinical and Molecular Findings of Tunisian Patients with RASopathies.

ABSTRACT: Noonan syndrome (NS) and related disorders, which are now summarized under the term RASopathies, are caused by germline mutations in genes encoding protein components of the Ras/mitogen-activated protein kinase pathway. In this study, we evaluated the clinical and molecular spectrum of 21 Tunisian patients, recruited by a cardiology unit, for whom RASopathy diagnosis was suspected by clinical geneticists. Overall, 19 patients had a clinical diagnosis of NS and 2 were classified as having Cardiofaciocutaneous (CFC) syndrome. In 52% (n = 11) of patients, a RASopathy has been molecularly confirmed. Mutations in PTPN11 and SOS1 genes were found in patients with diagnosis of NS and BRAF gene mutations in patients with CFC syndrome. As reported from other cohorts, mutations in exons 3 and 8 of the PTPN11 gene predominated in Tunisian NS patients. A very uncommon PTPN11 mutation c.5C>T (p.T2I), the functional consequences of which have so far remained unclear, was identified in one patient. As biased by the mode of recruitment, all patients included in this study had a congenital heart defect, with pulmonary valve stenosis being the most frequent one. Short stature and developmental abnormalities were present in mutation-positive cases. This is the first molecular study in patients from southern Tunisia with RASopathy diagnosis.

SUBMITTER: Louati R

PROVIDER: S-EPMC4188152 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Clinical and Molecular Findings of Tunisian Patients with RASopathies.

Louati Rim R Abdelmoula N Bouayed NB Trabelsi Imen I Abid Dorra D Lissewski Christina C Kharrat Najla N Kamoun Samir S Zenker Martin M Rebai Tarek T

Molecular syndromology 20140523 5

Noonan syndrome (NS) and related disorders, which are now summarized under the term RASopathies, are caused by germline mutations in genes encoding protein components of the Ras/mitogen-activated protein kinase pathway. In this study, we evaluated the clinical and molecular spectrum of 21 Tunisian patients, recruited by a cardiology unit, for whom RASopathy diagnosis was suspected by clinical geneticists. Overall, 19 patients had a clinical diagnosis of NS and 2 were classified as having Cardiof ...[more]

PMID: 25337068

Similar Datasets

Project description:ImportanceClinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.ObjectiveTo perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.Design, setting, and patientsObservational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.Main outcomes and measuresWhole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.ResultsA molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.Conclusions and relevanceWhole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.

Project description:BackgroundOcular cystinosis is a rare autosomal recessive disorder characterized by intralysosomal cystine accumulation in renal, ophthalmic (cornea, conjunctiva), and other organ abnormalities. Patients with ocular cystinosis are mostly asymptomatic and typically experience mild photophobia due to cystine crystals in the cornea observed accidently during a routine ocular examination. The ocular cystinosis is associated with different mutations in CTNS gene. Cysteamine therapy mostly corrects the organ abnormalities.MethodsThis study was performed in collaboration with the department of ophthalmology of Farhat Hached Hospital. The Optical Coherence Tomography (OCT) of the cornea and retinal photography were used to search cystine crystals within the corneas and conjunctiva in eight Tunisian patients. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the entire CTNS gene.ResultsThe studied patients were found to have cystine crystal limited anterior corneal stroma and the conjunctiva associated with retinal crystals accumulation. CTNS gene sequencing disclosed 7 mutations: three missense mutations (G308R, p.Q88K, and p.S139Y); one duplication (C.829dup), one framshift mutation (p.G258f), one splice site mutation (c.681 + 7delC) and a large deletion (20,327-bp deletion). Crystallographic structure analysis suggests that the novel mutation p.S139Y is buried in a first transmembrane helix closed to the lipid bilayer polar region, introducing a difference in hydrophobicity which could affect the hydrophobic interactions with the membrane lipids. The second novel mutation p.Q88K which is located in the lysosomal lumen close to the lipid membrane polar head region, introduced a basic amino acid in a region which tolerate only uncharged residue. The third missense mutation introduces a positive change in nonpolar tail region of the phospholipid bilayer membrane affecting the folding and stability of the protein in the lipid bilayer.ConclusionsOur data demonstrate that impaired transport of cystine out of lysosomes is the most common, which is obviously associated with the mutations of transmembrane domains of cystinosine resulting from a total loss of its activity.

Dataset Information

Clinical and Molecular Findings of Tunisian Patients with RASopathies.

Publications

Clinical and Molecular Findings of Tunisian Patients with RASopathies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets