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Genetics, Génétique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Endocrinopathies, Hypothalamus. Hypophyse. Epiphyse (pathologie), Hypothalamus. Hypophysis. Epiphysis (diseases), Pathologie non tumorale. Résistance tissu cible. Tumeurs bénignes, Non tumoral diseases. Target tissue resistance. Benign neoplasms, Genetique medicale, Medical genetics, Généralités. Conseil génétique, General aspects. Genetic counseling, Endocrinopathie, Endocrinopathy, Endocrinopatía, Hypophyse pathologie, Pituitary diseases, Hipófisis patología, Malformation, Malformación, Association, Asociación, Génétique, Genetics, Genética, Homme, Human, Hombre, Hypoplasie, Hypoplasia, Hipoplasia, Insuffisance hypophysaire, Hypophyseal insufficiency, and Insuficiencia hipofisaria

Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.

Genetics, Génétique, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Genetique des eucaryotes. Evolution biologique et moleculaire, Genetics of eukaryotes. Biological and molecular evolution, Génétique classique, génétique quantitative, hybrides, Classical genetics, quantitative genetics, hybrids, Homme, Human, Sciences medicales, Medical sciences, Otorhinolaryngologie. Stomatologie, Otorhinolaryngology. Stomatology, Face, maxillaires, dents, parodonte: maladies, sémiologie, Facial bones, jaws, teeth, parodontium: diseases, semeiology, Maladies non tumorales, Non tumoral diseases, Genetique medicale, Medical genetics, Généralités. Conseil génétique, General aspects. Genetic counseling, Cavité buccale pathologie, Oral cavity disease, Cavidad bucal patología, Maladie congénitale, Congenital disease, Enfermedad congénita, Malformation, Malformación, Stomatologie, Stomatology, Estomatología, Bec de lièvre, Cleft lip, Labio leporino, Carte génétique, Genetic mapping, Mapa genético, Chromosome A2, Cromosoma A2, Chromosome C9, Cromosoma C9, Fente palatine, Cleft palate, Palato hendido, Gène, Gene, Gen, Génome, Genome, Genoma, Génétique, Genetics, Genética, Homme, Human, Hombre, Locus, Multiple, Múltiple, Métaanalyse, Metaanalysis, Meta-análisis, Fente labiale, and Labio hendido

Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD] = 6.6). In addition, meta-analyses with the addition of results from 186 more families (six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P = .0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder.

Genetics, Génétique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Neurologie, Neurology, Sclérose en plaques et variantes. Syndrome de guillain barré et autres polyradiculonévrites inflammatoires. Leucoencéphalites, Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis, Maladie inflammatoire, Inflammatory disease, Enfermedad inflamatoria, Système nerveux central pathologie, Central nervous system disease, Sistema nervosio central patología, Système nerveux pathologie, Nervous system diseases, Sistema nervioso patología, Allèle, Allele, Alelo, Apolipoprotéine E, Apolipoprotein E, Apolipoproteína E, Déterminisme génétique, Genetic determinism, Determinismo genético, Exploration, Exploración, Facteur risque, Risk factor, Factor riesgo, Génotype, Genotype, Genotipo, Homme, Human, Hombre, Indice gravité, Severity score, Indicio gravedad, Pathogénie, Pathogenesis, Patogenia, Physiopathologie, Pathophysiology, Fisiopatología, Polymorphisme mononucléotide, Single nucleotide polymorphism, Polimorfismo mononucleótido, Polymorphisme, Polymorphism, Polimorfismo, Sclérose en plaques, Multiple sclerosis, and Esclerosis en placa

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, with a complex etiology that includes a strong genetic component. The contribution of the major histocompatibility complex (MHC) has been established in numerous genetic linkage and association studies. In addition to the MHC, the chromosome 19q13 region surrounding the apolipoprotein E (APOE) gene has shown consistent evidence of involvement in MS when family-based analyses were conducted. Furthermore, several clinical reports have suggested that the APOE-4 allele may be associated with more-severe disease and faster progression of disability. To thoroughly examine the role of APOE in MS, we genotyped its functional alleles, as well as seven single-nucleotide polymorphisms (SNPs) located primarily within 13 kb of APOE, in a data set of 398 families. Using family-based association analysis, we found statistically significant evidence that an SNP haplotype near APOE is associated with MS susceptibility (P = .005). An analysis of disease progression in 614 patients with MS from 379 families indicated that APOE-4 carriers are more likely to be affected with severe disease (P = .03 ), whereas a higher proportion of APOE-2 carriers exhibit a mild disease course (P = .02).