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Affected Siblings (affected + sibling)

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Medical Sciences62%

Terms modified by Affected Siblings

  • affected sibling pair
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    Selected Abstracts

    Dystrophic epidermolysis bullosa pruriginosa is not associated with frequent FLG gene mutations

    BRITISH JOURNAL OF DERMATOLOGY, Issue 2 2008
    H. Schumann
    Summary Background, Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr; OMIM 604129) is a rare manifestation of dystrophic epidermolysis bullosa (DEB), characterized by pruritus, nodular prurigo-like lesions and fragility of the skin mainly in the extremities. Fewer than 40 patients with autosomal dominant or recessive inheritance, or sporadic DEB-Pr, have been described in the literature. Objectives, To disclose mutations in DEB-Pr and to elucidate the role of other pathogenic factors which may influence the pruriginous phenotype. Methods, Seven patients with typical clinical features of DEB-Pr were studied. Results, In all patients, mutations in the gene encoding collagen VII (COL7A1) were disclosed, two of them novel (p.G2623V, p.E2736K). Three mutations were dominant, three recessive and one de novo. In the families with dominant DEB there were one or more members with DEB-Pr, but also at least one affected sibling who did not develop DEB-Pr. In six of seven patients, the clinical history revealed factors that initially induced pruritus, such as atopy, pregnancy, thyroid hormone imbalance, diabetes, infections and contact sensitization. Common filaggrin mutations were ruled out in all patients and normal filaggrin staining was found in the skin samples. Conclusions, DEB-Pr develops as a result of COL7A1 gene mutations and acquired phenotype-modifying factors. Filaggrin mutations did not contribute to the pruriginous phenotype in the present patient cohort. [source]

    The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interaction

    INFLAMMATORY BOWEL DISEASES, Issue 1 2005
    Marie Pierik MD
    Abstract Background and Aims: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 × smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. Patients and Methods: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. Results: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P , 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively). Conclusions: The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene-environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4. [source]

    No linkage of the interleukin-4 receptor locus on chromosome 16p11.2-12.1 with sarcoidosis in German multiplex families

    INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2002
    A. Bohnert
    Summary We typed 241 members of 62 sarcoidosis families with 136 affected siblings for three single nucleotide polymorphisms of the interleukin-4 receptor alpha-chain gene (IL4R). Allele frequencies in patients were compared to those of healthy unrelated control individuals. The segregation of the three-point IL4R haplotypes completed by two flanking highly polymorphic microsatellite polymorphisms revealed no evidence for linkage of the IL4R gene locus with sarcoidosis. [source]

    Familial associations of intense preoccupations, an empirical factor of the restricted, repetitive behaviors and interests domain of autism

    THE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 8 2009
    Christopher J. Smith
    Background:, Clinical heterogeneity of autism likely hinders efforts to find genes associated with this complex psychiatric disorder. Some studies have produced promising results by restricting the sample according to the expression of specific familial factors or components of autism. Previous factor analyses of the restricted, repetitive behaviors and interest (RRBI) domain of autism have consistently identified a two-factor model that explains a moderate amount of variance. The identification of additional factors may explain more variance in the RRBI domain and provide an additional component of autism that may help in the identification of underlying genetic association. Methods:, We conducted factor analyses of RRBI symptoms with a sample that included verbal subjects meeting full criteria for autism aged 5 to 22 years (n = 245). Among affected sibling pairs (n = 126) we examined the familial aggregation of the identified factors. We also examined the associations of the factors with autism-related personality traits in fathers and mothers (n = 50). Results:, The previously identified two-factor model , insistence on sameness (IS) and repetitive stereotypic motor behaviors (RSMB) , was replicated in our sample. Next, a second factor analysis that included the item for verbal rituals resulted in a four-factor model , IS, ,simple' RSMB, ,complex' RSMB, and a fourth factor including symptoms associated with intense preoccupations (IP). Of these four, both IS and IP were significantly familial among affected siblings, but only IP was significantly correlated with the broader autism phenotype traits of rigidity and aloofness in fathers. Conclusions:, The results support previous evidence for the IS factor, its familiality, and the identification of IP as an additional strong candidate trait for genetic studies of autism. [source]

    Spectrum and Frequency of SLC26A4 Mutations Among Czech Patients with Early Hearing Loss with and without Enlarged Vestibular Aqueduct (EVA)

    ANNALS OF HUMAN GENETICS, Issue 4 2010
    Radka Pourová
    Summary Mutations in SLC26A4 cause Pendred syndrome (PS) , hearing loss with goitre , or DFNB4 , non-syndromic hearing loss (NSHL) with inner ear abnormalities such as Enlarged Vestibular Aqueduct (EVA) or Mondini Dysplasia (MD). We tested 303 unrelated Czech patients with early hearing loss (298 with NSHL and 5 with PS), all GJB2 -negative, for SLC26A4 mutations and evaluated their clinical and radiological phenotype. Among 115 available HRCT/MRI scans we detected three MD (2.6%), three Mondini-like affections (2.6%), 16 EVA (13 bilateral , 19.2% and 15.6% respectively) and 61 EVA/MD-negative scans (73.4%). We found mutation(s) in 26 patients (8.6%) and biallelic mutations in eight patients (2.7%) out of 303 tested. In 18 of 26 (69%) patients, no second mutation could be detected even using MLPA. The spectrum of SLC26A4 mutations in Czech patients is broad without any prevalent mutation. We detected 21 different mutations (four novel). The most frequent mutations were p.Val138Phe and p.Leu445Trp (18% and 8.9% of pathogenic alleles respectively). Among 13 patients with bilateral EVA, six patients (50%) carry biallelic mutations. In EVA -negative patients no biallelic mutations were found but 4.9% had monoallelic mutations. SLC26A4 mutations are present mostly in patients with EVA/MD and/or progressive HL and those with affected siblings. [source]

    A Novel Point Variant in NTRK3, R645C, Suggests a Role of this Gene in the Pathogenesis of Hirschsprung Disease

    ANNALS OF HUMAN GENETICS, Issue 1 2009
    R. M. Fernández
    Summary Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the myenteric and submucosal plexuses due to a defect in the migration process of neural crest neuroblasts. Manifestation of the disease has been linked to the dysfunction of two principal signalling pathways involved in the enteric nervous system (ENS) formation: the RET-GDNF and the EDN3-EDNRB receptor systems. However, the NTF3/NTRK3 signalling pathway plays an essential role in the development of the ENS suggesting a potential role for those genes in the pathogenesis of HSCR. We have sought to evaluate the candidature of the NTRK3 gene, which encodes the TrkC receptor, as a susceptibility gene for Hirschsprung disease. Using dHPLC technology we have screened the NTRK3 coding region in 143 Spanish HSCR patients. A total of four previously described polymorphisms and 12 novel sequence variants were detected. Of note, the novel R645C mutation was detected in 2 affected siblings of a HSCR family also carrying a RET splicing mutation. Using bioinformatics tools we observed that the presence of an additional cysteine residue might implicate structural alterations in the mutated protein. We propose haploinsufficiency as the most probable mechanism for the NTRK3 R645C mutation. NTRK3 and RET mutations in this family only appear together in the HSCR patients, suggesting that they per se are necessary but not sufficient to produce the phenotype. In addition, it is quite probable that the contribution of other still unidentified modifier genes, may be responsible for the different phenotypes (length of aganglionosis) in the two affected members. [source]

    A variant TGFBI corneal dystrophy from G623D mutation with an unusual amyloidogenic phenotype

    ACTA OPHTHALMOLOGICA, Issue 2009
    HT AGOSTINI
    Purpose To present a unique corneal dystrophy never before described in a German family carrying the Gly623Asp mutation of the TGFBI gene with late clinical onset. Methods Clinical documentation and isolation of genomic DNA from peripheral blood leucocytes were obtained from each family member examined. Exons 3, 4, 5, and 11 to 14 of the TGFBI gene were sequenced. 5 corneal buttons of 3 affected siblings were excised at the time of penetrating keratoplasty. Light and electron microscopic examination were performed including immunohistochemistry with antibodies against Keratoepithelin (KE) 2 and 15. Results Specimens showed changes in Bowman's layer and the adjacent stroma. Congo red-positive amyloid deposits were found within the epithelium in one cornea, in Bowman's layer and in the anterior stroma of all specimens, also showing KE2- but not KE15-immunostaining. EM revealed deposits located in the anterior stroma and Bowman's layer and the basal area of some epithelial cells. These areas were strongly Alcian blue-positive but negative in the Masson-Trichrom-stain. Only affected patients had a heterozygous missense mutation in exon 14 of the TGFBI gene (G->A transition at nucleotide 1915) with the change Gly623Asp in the keratoepithelin protein. Conclusion In contrast to the patient carrying the Gly623Asp mutation of the TGFBI gene described by Afshari et al., our cases presented with Salzmann nodular degeneration like clinical features with KE2 positive amyloid. The reason for this now "meeting the expectation histological phenotype" is unclear. The histological findings emphasize that this is a unique corneal dystrophy which shares no clinical characteristics with Reis-Bücklers dystrophy and should be treated as a distinct entity. [source]

    Homozygous LMNA mutation R527C in atypical Hutchinson,Gilford progeria syndrome: evidence for autosomal recessive inheritance

    ACTA PAEDIATRICA, Issue 8 2009
    Lili Liang
    Abstract Aim:, To describe two Chinese siblings of atypical Hutchinson,Gilford progeria syndrome (HGPS), with genetic diagnosis and special clinical manifestation. Methods:, We screened the LMNA gene in four members of a consanguineous family, in which two children were suffering from atypical HGPS. Besides general HGPS features, such as growth retardation and characteristic appearance, special clinical phenotypes including disorders of digestive system and severe skeletal damages were observed. Results:, Homozygous mutation 1579C>T, which predicts R527C, was identified in the exon 9 of LMNA among the affected siblings. Heterozygous carrier status 1579C>T was detected in both of the asymptomatic parents. Conclusion:, Homozygous mutation R527C in LMNA yields atypical HGPS, and it suggests an autosomal recessive inheritance in this family. [source]