RESEARCH ARTICLE Multiple Copy Number Variants in a Pediatric Patient with Hb H Disease and Intellectual Disability Karen G. Scheps, 1,2 Liliana Francipane, 3 Juli an Nevado, 4,5 Nora Basack, 6 Myriam Attie, 6 Marı ´a Fernanda Bergonzi, 3 Gloria E. Cerrone, 1,2 Pablo Lapunzina, 4,5 and Viviana Varela 1,2 * 1 C atedra de Gen etica, Facultad de Farmacia y Bioquı ´mica, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina 2 INIGEM (Instituto de Inmunologı ´a, Gen etica y Metabolismo), CONICET- Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina 3 Divisi on Gen etica, Hospital de Clı ´nicas “Jos e de San Martı ´n”, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina 4 INGEMM (Instituto de Gen etica M edica y Molecular), Hospital Universitario La Paz-IdiPaz, Universidad Aut onoma de Madrid, Madrid, Spain 5 CIBERER (Centro de Investigaci on Biom edica en Red de Enfermedades Raras), Madrid, Spain 6 Divisi on Hematologı ´a, Hospital de Ni~ nos “Dr. Ricardo Guti errez”, Ciudad de Buenos Aires, Buenos Aires, Argentina Manuscript Received: 1 October 2015; Manuscript Accepted: 11 December 2015 Two distinct syndromes that link a-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 a-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 -a 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 heterozy- gous 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. Ó 2016 Wiley Periodicals, Inc. Key words: ATR-16; CNV; intellectual disability; MLPA; SNP- array; Hb H INTRODUCTION a-thalassemia (thal) (OMIM: 604131) has been associated, rarely, with intellectual disability. Two distinct syndromes have been des- cribed: ATR-16 (alpha Thalassemia-mental retardation syndrome chromosome 16-related; OMIM: 141750), consequence of deletions that remove and extend beyond the a-globin cluster and ATR-X (OMIM: 301040), due to mutations in trans with the a-globin cluster, that affect the ATRX gene (Xq13.1-q21.2) [McPherson et al., 1995] which encodes a member of the SWI/SNF family involved in the regulation of the expression of the a-globin genes. The affected individuals present relatively uniform clinical features and severe intellectual disability [Galanello and Cao, 2011]. On the other hand, ATR-16 is defined as a contiguous gene deletion syndrome resulting in haploinsufficiency of the a-globin gene cluster and genes involved in intellectual disability, in the telomeric region of the short arm of chromosome 16. Until now, 11 cases due to deletions, between 900 and 1,700 kb that lead to pure monosomy of 16p13.3 have been reported. The affected patients present heterogeneous clinical signs: various develop- mental abnormalities (e.g., skeletal abnormalities and facial Conflict of interest: none. Grant sponsor: UBACyT; Grant number: 20020120200092BA.  Correspondence to: Dra. Viviana Varela, Facultad de Farmacia y Bioquı´mica, Universidad de Buenos Aires, Junin 956, 1113 Ciudad de Buenos Aires, Argentina. E-mail: vvarela@ffyb.uba.ar Article first published online in Wiley Online Library (wileyonlinelibrary.com): 11 January 2016 DOI 10.1002/ajmg.a.37532 How to Cite this Article: Scheps KG, Francipane L, Nevado J, Basack N, Attie M, Bergonzi MF, Cerrone GE, Lapunzina P, Varela V. 2016. Multiple copy number variants in a pediatric patient with Hb H disease and intellectual disability. Am J Med Genet Part A 170A:986–991. Ó 2016 Wiley Periodicals, Inc. 986