Combined segregation and linkage analysis of HLA markers in familial psoriasis
Sun‐Wei GuoStefan JenischPhilip E. StuartEthan M. LangeDebra KukurugaRajan P. NairTilo HenselerJohn J. VoorheesEnno ChristophersJames T. Elder
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Linkage Disequilibrium
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Abstract Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3 . Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance.
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Hemifacial microsomia
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To test the hypothesis that a multiple sclerosis susceptibility (MSS) gene is linked to the HLA loci, formal linkage analysis was conducted on 40 multiplex families, 20 each from the Seattle and Los Angeles areas. The computer program LIPED was utilized. A dominant model of inheritance was assumed. Penetrance values of 0.05, 0.35, and 0.67 were entered into the analyses, and an age‐of‐onset correction was incorporated. The resulting lod scores were supportive of linkage at the lower penetrance levels. The maximum lod score, 2.411, at an estimated recombination fraction of 0.10 in both males and females, was generated at a penetrance value of 0.05. With a penetrance value of 0.67, the lod scores did not support linkage. Under an autosomal dominant model of inheritance, the results were supportive of linkage when the presumed penetrance of the MSS gene is low. The results also confirmed the importance of incorporating an age‐of‐onset correction into linkage analyses.
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Vesicoureteral reflux (VUR) (OMIM %193000), a common cause of childhood renal failure, is strongly influenced by hereditary factors. Familial VUR most closely conforms to autosomal-dominant inheritance, but because of variable penetrance and expressivity, large multigenerational pedigrees tractable to linkage analysis have been difficult to ascertain. A single genome-wide study of familial VUR has demonstrated linkage to chromosome 1p13, with 78% locus heterogeneity. Previous studies in humans have also suggested loci on chromosomes 6p21, 10q26, and 19q13, whereas mutations in ROBO2 were recently reported in some patients with VUR. Replication of these studies was attempted in seven previously undescribed families from Italy and the United States. Simulation studies, assuming 50% locus heterogeneity, showed that these kindreds had 85% power to replicate linkage and 53% power to achieve genome-wide significance at candidate intervals. Thirty-five markers on chromosomes 1p13, 3p12, 6p21, 10q26, and 19q13 were genotyped and analysis of linkage under a variety of models was performed. Parametric analysis excluded linkage to all candidate loci under genetic homogeneity; moreover, the data did not support statistically significant linkage under models of locus heterogeneity. Similarly, nonparametric, allele-sharing analysis did not reveal any evidence of linkage at any of the loci tested. Thus, despite sufficient power, linkage of familial VUR to previously reported candidate intervals could not be replicated. These data demonstrate substantial genetic heterogeneity of VUR and suggest that mapping strategies relying on a large number of kindreds or single "loaded" pedigrees will be most effective to achieve replication or detection of linkage.
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In their interesting and recent state-of-the-art study, Burkett and Hershberger ([1][1]) stated that “familial dilated cardiomyopathy (DCM) demonstrates incomplete penetrance, variable expression, and significant locus and allelic heterogeneity, making clinical and genetic diagnosis complex.”
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