title: Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome.
abstract: Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions.
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Distrito Federal, México.
authors.forename: M A
authors.initials: MA
authors.lastname: Alcántara-Ortigoza
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Distrito Federal, México.
authors.forename: B
authors.initials: B
authors.lastname: García-de Teresa
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Distrito Federal, México.
authors.forename: A
authors.initials: A
authors.lastname: González-Del Angel
authors.affiliation: Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Distrito Federal, México.|Unidad de Medicina Genómica, Hospital General de México, Distrito Federal, México.
authors.forename: J
authors.initials: J
authors.lastname: Berumen
authors.affiliation: Unidad de Medicina Genómica, Hospital General de México, Distrito Federal, México.
authors.forename: M
authors.initials: M
authors.lastname: Guardado-Estrada
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Distrito Federal, México.
authors.forename: L
authors.initials: L
authors.lastname: Fernández-Hernández
authors.affiliation: Servicio de Genética. Hospital de Alta Especialidad PEMEX Picacho Sur, Distrito Federal, México.
authors.forename: J I
authors.initials: JI
authors.lastname: Navarrete-Martínez
authors.affiliation: Médico Residente de Pediatría, Instituto Nacional de Pediatría, Distrito Federal, México.
authors.forename: M
authors.initials: M
authors.lastname: Maza-Morales
authors.affiliation: Médico Residente de Genética Médica, Departamento de Genética Humana, Instituto Nacional de Pediatría, Distrito Federal, México.
authors.forename: R
authors.initials: R
authors.lastname: Rius-Domínguez
mesh_terms: D000293:Adolescent; D000483:Alleles; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D015321:Gene Rearrangement; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008800:Mexico; D016532:Mucopolysaccharidosis II / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: D006023:Glycoproteins; C018322:IDS protein, human
keywords: AFF2 gene; DNA microarray; Mexican population; idiopathic thrombocytopenic purpura; idursulfase; lysosomal storage disease; mucopolysaccharidosis type II; prenatal diagnosis; somatic and germline mosaicism