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.

ATR-16 syndrome: mechanisms linking monosomy to phenotype

“…Together these observations suggest that monosomy for 16p13.3 unmasks the effects of other variants genome-wide. This is supported by findings in SCH who has a very similar deletion to BAR and is more severely affected possibly owing to the presence of other CNVs 28. At the other end of the spectrum, large ATR-16 deletions may be associated with relatively mild abnormalities.…”

ATR16 Syndrome: Mechanisms Linking Monosomy to Phenotype

“…1 5 Together these observations suggest that monosomy for 16p13.3 unmasks 1 6 the effects of other variants genome-wide. This is supported by findings in SCH who 1 7 has a very similar deletion to BAR and may be more severely affected owing to the 1 8 presence of other CNVs (Scheps et al, 2016). At the other end of the spectrum, 1 9 large ATR-16 deletions may be associated with relatively mild abnormalities.…”

Convergence of specified RUNX2, SALL1, and SAMD9 variants permits normal global immune and endocrine function despite bone marrow hypocellularity and reduced ovarian reserve

“…RUNX2 is considered to be a centrally regulating transcription factor for osteoblast and chondrocyte differentiation and overall skeletal architecture [22,23]. Some 80 variants in RUNX2 have been identi ed [1,24] and while heterozygous loss of function mutations can lead to cleidocranial dysplasia, this is inconsistent [25]. Triplication [26] or quadruplication [27] of RUNX2 accompanies more serious syndromic phenotypes, including coronal/sagittal synostosis or pan-craniosynostosis [26,27] suggesting a dosage effect [28].…”