Multiple Copy Number Variants in a pediatric patient with Hb H disease and intellectual disability, Journal Cover

KAREN G. SCHEPS; FRANCIPANE LILIANA; JULIÁN NEVADO; NORA BASACK; MYRIAM ATTIE; MARÍA FERNANDA BERGONZI; GLORIA E. CERRONE; PABLO LAPUNZINA; VIVIANA VARELA

American Journal of Medical Genetics Part A

Wiley

Año: 2016 vol. 170 p. 1 - 1

Two distinct syndromes that link a-thalassemia and intellectualdisability (ID)havebeen described:ATR-X,due tomutations in theATRX gene, and ATR-16, a contiguous gene deletion syndrome inthe telomeric region of the short arm of chromosome 16. A criticalregion where the candidate genes for the ID map has beenestablished. In a pediatric patient with Hemoglobin H disease,dysmorphic features and ID, 4 novel and clinically relevant CopyNumber Variants were identified. PCR-GAP, MLPA and FISHanalyses established the cause of the a-thalassemia. SNP-arrayanalysis 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 -a3.7 mutation andthe 1.51 Mb in 16p13.3 are involved in the alpha-thalassemicphenotype. However, the critical region for ATR-16 cannot benarrowed down. The deletion affecting 6p21.1 removes the first 2exons and part of intron 2 of the RUNX2 gene. Although heterozygousloss of function mutations affecting this gene have beenassociated with cleidocranial dysplasia, the patient does not exhibitpathognomonicsigns of this syndrome,possiblydue to the fact thatthe isoform d of the transcription factor remains unaffected. Thisworkhighlights the importanceof searchingfor cryptic deletions inpatients with ID and reiterates the need of the molecular analysiswhen it is associated to microcytic hypochromic anemia withnormal iron status.