RESUMEN
Autosomal recessive ataxias are heterogeneous group of disorders characterized by cerebellar atrophy and peripheral sensorimotor neuropathy. Molecular characterization of this group of disorders identified a number of genes contributing to these overlapping phenotypes. Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive form of ataxia caused by mutations in the SETX gene. We report on a consanguineous family with autosomal recessive inheritance and clinical characteristics of AOA2, and no mutations in the SETX gene. We mapped the AOA locus in this family to chromosome 17p12-p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis.
Asunto(s)
Apraxias/genética , Ataxia Telangiectasia/genética , Ataxia/genética , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Hipoalbuminemia/genética , Mutación Missense , Fosfatidilinositol 3-Quinasas/genética , Adolescente , Adulto , Animales , Apraxias/diagnóstico , Ataxia/diagnóstico , Ataxia Telangiectasia/diagnóstico , Encéfalo/patología , Ataxia Cerebelosa/congénito , Consanguinidad , ADN Helicasas , Femenino , Orden Génico , Ligamiento Genético , Homocigoto , Humanos , Hipoalbuminemia/diagnóstico , Imagen por Resonancia Magnética , Masculino , Ratones , Enzimas Multifuncionales , Linaje , Fenotipo , ARN Helicasas/genética , Relaciones entre Hermanos , Adulto JovenRESUMEN
PURPOSE: Copy number variants are an important source of human genome diversity. The widespread distribution of hemizygous copy number variants in the DNA of healthy humans suggests that haploinsufficiency is largely tolerated. However, little is known about the extent to which corresponding nullizygosity (two-copy deletion) is similarly tolerated. METHODS: We analyzed a cohort of first cousin unions to enrich for shared parental hemizygous events and tested their Mendelian inheritance in offspring. RESULTS: Analysis of autozygous DNA blocks (autozygome) in the offspring not only proved an efficient method of mapping "dispensable" DNA but also revealed potential selective bias against the occurrence of nullizygous changes. This bias was not restricted to genic copy number variants and was not accounted for by a high rate of miscarriages. CONCLUSIONS: The autozygome is an efficient way to map dispensable segments of DNA and may reveal selective bias against nullizygosity in healthy individuals.
Asunto(s)
Mapeo Cromosómico/métodos , Variaciones en el Número de Copia de ADN/genética , Hemicigoto , Eliminación de Secuencia/genética , Estudios de Cohortes , Consanguinidad , ADN/sangre , Femenino , Dosificación de Gen , Genoma Humano , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , LinajeRESUMEN
PURPOSE: To perform linkage analysis on an inbred family with members who exhibit different phenotypic forms of childhood strabismus. METHODS: Prospective clinical examination and linkage analysis. RESULTS: three of the ten siblings and their cousin each had a different phenotypic form of childhood strabismus: infantile esotropia with convergence excess, esotropia associated with anisometropic amblyopia, unilateral esotropic Duane syndrome, and monocular elevation deficiency. Linkage analysis for the four strabismic individuals, an unaffected sibling, and the unaffected parents identified a single disease locus on chromosome 16p13.12-p12.3 (Ensembl cytogenetic band) with a 2.5 maximum logarithm of odds score. The region is 6 MB in size and comprises 80 genes. DISCUSSION: Linkage analysis in this unique family suggests that childhood strabismus can be recessive and that different phenotypic forms of childhood strabismus can share the same underlying genotype.