title: Multiple copy number variants in a pediatric patient with Hb H disease and intellectual disability.
abstract: Two distinct syndromes that link α-thalassemia and intellectual disability (ID) have been described: ATR-X, due to mutations in the ATRX gene, and ATR-16, a contiguous gene deletion syndrome in the telomeric region of the short arm of chromosome 16. A critical region where the candidate genes for the ID map has been established. In a pediatric patient with Hemoglobin H disease, dysmorphic features and ID, 4 novel and clinically relevant Copy Number Variants were identified. PCR-GAP, MLPA and FISH analyses established the cause of the α-thalassemia. SNP-array analysis revealed the presence of 4 altered loci: 3 deletions (arr[hg19]Chr16(16p13.3; 88,165-1,507,988) x1; arr[hg19]Chr6(6p21.1; 44,798,701-45,334,537) x1 and arr[hg19]Chr17(17q25.3; 80,544,855-81,057,996) x1) and a terminal duplication (arr[hg19]Chr7(7p22.3-p22.2; 4,935-4,139,785) x3). The -α(3.7) mutation and the ∼1.51 Mb in 16p13.3 are involved in the alpha-thalassemic phenotype. However, the critical region for ATR-16 cannot be narrowed down. The deletion affecting 6p21.1 removes the first 2 exons and part of intron 2 of the RUNX2 gene. Although heterozygous loss of function mutations affecting this gene have been associated with cleidocranial dysplasia, the patient does not exhibit pathognomonic signs of this syndrome, possibly due to the fact that the isoform d of the transcription factor remains unaffected. This work highlights the importance of searching for cryptic deletions in patients with ID and reiterates the need of the molecular analysis when it is associated to microcytic hypochromic anemia with normal iron status.
authors.affiliation: Cátedra de Genética, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.|INIGEM (Instituto de Inmunología, Genética y Metabolismo), CONICET- Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Karen G
authors.initials: KG
authors.lastname: Scheps
authors.affiliation: División Genética, Hospital de Clínicas "José de San Martín", Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Liliana
authors.initials: L
authors.lastname: Francipane
authors.affiliation: INGEMM (Instituto de Genética Médica y Molecular), Hospital Universitario La Paz-IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain.|CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Madrid, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Nevado
authors.affiliation: División Hematología, Hospital de Niños "Dr. Ricardo Gutiérrez", Ciudad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Nora
authors.initials: N
authors.lastname: Basack
authors.affiliation: División Hematología, Hospital de Niños "Dr. Ricardo Gutiérrez", Ciudad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Myriam
authors.initials: M
authors.lastname: Attie
authors.affiliation: División Genética, Hospital de Clínicas "José de San Martín", Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: María Fernanda
authors.initials: MF
authors.lastname: Bergonzi
authors.affiliation: Cátedra de Genética, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.|INIGEM (Instituto de Inmunología, Genética y Metabolismo), CONICET- Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Gloria E
authors.initials: GE
authors.lastname: Cerrone
authors.affiliation: INGEMM (Instituto de Genética Médica y Molecular), Hospital Universitario La Paz-IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain.|CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Cátedra de Genética, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.|INIGEM (Instituto de Inmunología, Genética y Metabolismo), CONICET- Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Viviana
authors.initials: V
authors.lastname: Varela
mesh_terms: D002648:Child; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D019066:Facies; D056726:Genetic Association Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D017085:alpha-Thalassemia / Q000175:diagnosis* / Q000235:genetics*
keywords: ATR-16; CNV; Hb H; MLPA; SNP-array; intellectual disability