Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation

Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, 05403-900 São Paulo, Brazil.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 12/2004; 130A(4):378-83. DOI: 10.1002/ajmg.a.30270
Source: PubMed


Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30-50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with downslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene-gene or gene-environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first-degree relatives should also be tested for the specific mutation.

9 Reads
  • Source
    • "The fact that different RASopathy genes can be associated with multiple disorders, or with a unique presentation of a disorder, underscores the complexity of the molecular genetic basis of NS. Indeed, the clinical presentation of NS and related disorders can vary widely across generations within a family (Bertola et al. 2004) and can also change considerably across an individual's lifespan. These findings suggest that a great deal of the variability in how a person expresses a RASopathy syndrome depends on factors other than the individual's specific genotype. "

    09/2015; DOI:10.1007/s40817-015-0005-5
  • Source
    • "In sum, the ALDH1A2 mutations that we describe in TOF may not be fully penetrant. However, non-penetrance is not restricted to the mutations we described, but is, rather, a common feature in most, if not all, of the described genes that may cause CHD in humans such as PTPN11 in Noonan Syndrome [47], KCNQ1 in Long QT Syndrome [48] and troponin T in Familial Hypertrophic Cardiomyopathy [49]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus. One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay. We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls. In summary, our screen indicates that ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.
    BMC Medical Genetics 11/2009; 10(1):113. DOI:10.1186/1471-2350-10-113 · 2.08 Impact Factor
  • Source
    • "; Mendez and Opitz , 1985 ; Opitz , 1985 ] . Recently , it was shown that 40% of patients with clinically diagnosed Noonan syndrome carry heterozygous missense mutations in the PTPN11 gene , so cause and varability of the Noonan syndrome seem to be resolved independent of its clinical phenotype [ Musante et al . , 2003 ; Tartaglia et al . , 2003 ; Bertola et al . , 2004 ] . However , prenatal diagnosis of Noonan syndrome is still difficult , because genetic diagnosis is usually restricted to cases with a known paternal or maternal mutation [ Schlüter et al . , 2005 ] . On the basis of studies of congenital heart defects in fetuses with cystic hygroma colli , Kalousek and Seller [ 1987 ] proposed the pu"
    [Show abstract] [Hide abstract]
    ABSTRACT: The Anatomical collection of the Department of Anatomy and Cell Biology, Medical School of the University of Halle, Germany, comprises more than 8,000 specimens. Around 600 of them show congenital anomalies. The collection of abnormal human and animal fetuses began as the private collection of Johann Friedrich Meckel the Elder (1724-1774), his son Philipp Friedrich Theodor Meckel (1755-1803) and his grandson Johann Friedrich Meckel the Younger (1781-1833). Meckel the Younger founded the systematic science of developmental pathology. Radiographical techniques, computer tomographic (CT) methods, magnetic resonance imaging (MRI), and comparative genomic hybridization (CGH) were used to diagnose abnormal human fetuses in the Meckel-anatomical collections. Cystic hygroma colli was found in five of the human fetuses originally described by JF Meckel the Younger in 1826 and one of his students in 1819 [Hencke, 1819]. CGH analyses were used to test whether the observed cystic hygroma colli could be caused by chromosomal aneuploidies. CGH-ratio profiles of all chromosomes were apparently normal. PCR-based sex determination tests on ancient DNA were used to determine the fetal gonosomal constitution. It is likely that the Meckel specimens are among the oldest fetuses in which Ullrich-Turner "phenotype" has been diagnosed.
    American Journal of Medical Genetics Part A 01/2007; 143(2):119-28. DOI:10.1002/ajmg.a.31488 · 2.16 Impact Factor
Show more