CORRESPONDENCE
Deletions of 9q21.3 Including NTRK2 Are Associated With Severe Phenotype Miroslava Hancarova,* Alena Puchmajerova, Jana Drabova, Eliska Karaskova, Marketa Vlckova and Zdenek Sedlacek Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic Manuscript Received: 28 April 2014; Manuscript Accepted: 4 September 2014
TO THE EDITOR: We have read with interest the report “Novel Interstitial 2.6 Mb Deletion on 9q21 Associated With Multiple Congenital Anomalies” by Pua et al. [2014], describing a patient with craniofacial abnormalities, heart defect, bicornuate uterus, extremity deformities, hip dislocation, delayed myelination, and recurrent pneumonia, who died after respiratory decompensation at 14 months of age. The region deleted in the patient showed limited copy number variation (CNV) in both normal and affected individuals, and the article prompted reporting of additional variants of this region to better understand their pathogenicity and the role of individual genes. In the course of CNV analysis in children with developmental delay (DD) and/or autistic features using SNP arrays (Human CytoSNP-12 BeadChips, Illumina, San Diego, CA) we identified a 9q21.3 deletion of about 2 Mb, arr[hg19] 9q21.32–q21.33 (86,369,356 2, 86,595,071–88,357,495 1, 88,477,869 2) dn, as a sole aberration in a severely affected Czech patient (Fig. 1). The deletion breakpoints were most likely located in segmental duplications represented by the KIF27 gene on the proximal side and a rearranged non-processed KIF27 pseudogene (LOC389765) on the distal side (Fig. 2). The deletion removed 7 protein-coding RefSeq genes, KIF27, C9orf64, HNRNPK, RMI1, SLC28A3, NTRK2, and AGTPBP1 (or 8 genes including GKAP1 if the proximal breakpoint were centromeric from the segmental duplication), and also the MIR7–1 gene (Fig. 2). The deletion was confirmed using FISH with BAC clone RP11–59M22 (BlueGnome, Cambridge, UK) in the patient but in none of her parents. Subsequent SNP array analysis of the parents confirmed the de novo nature of the deletion and showed its paternal origin. The currently 13-year-old girl was the first child of healthy nonconsanguineous Czech parents aged 29 and 28, both university graduates. The second trimester biochemical screening in pregnancy showed values pointing to an increased risk of chromosome aberrations (AFP 0.89 MoM; uE3 0.68 MoM; HCG 3.16 MoM) but the fetal karyotype from amniotic fluid cells was normal. The girl was delivered at 42 weeks of gestation by Caesarean due to abnormal cardiotocography. The birth parameters were nearly normal: weight of 3,650 g (25th–50th centile), length of 50 cm (25th centile) and head circumference (HC) of 34 cm (
Deletions of 9q21.3 Including NTRK2 Are Associated With Severe Phenotype Miroslava Hancarova,* Alena Puchmajerova, Jana Drabova, Eliska Karaskova, Marketa Vlckova and Zdenek Sedlacek Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic Manuscript Received: 28 April 2014; Manuscript Accepted: 4 September 2014
TO THE EDITOR: We have read with interest the report “Novel Interstitial 2.6 Mb Deletion on 9q21 Associated With Multiple Congenital Anomalies” by Pua et al. [2014], describing a patient with craniofacial abnormalities, heart defect, bicornuate uterus, extremity deformities, hip dislocation, delayed myelination, and recurrent pneumonia, who died after respiratory decompensation at 14 months of age. The region deleted in the patient showed limited copy number variation (CNV) in both normal and affected individuals, and the article prompted reporting of additional variants of this region to better understand their pathogenicity and the role of individual genes. In the course of CNV analysis in children with developmental delay (DD) and/or autistic features using SNP arrays (Human CytoSNP-12 BeadChips, Illumina, San Diego, CA) we identified a 9q21.3 deletion of about 2 Mb, arr[hg19] 9q21.32–q21.33 (86,369,356 2, 86,595,071–88,357,495 1, 88,477,869 2) dn, as a sole aberration in a severely affected Czech patient (Fig. 1). The deletion breakpoints were most likely located in segmental duplications represented by the KIF27 gene on the proximal side and a rearranged non-processed KIF27 pseudogene (LOC389765) on the distal side (Fig. 2). The deletion removed 7 protein-coding RefSeq genes, KIF27, C9orf64, HNRNPK, RMI1, SLC28A3, NTRK2, and AGTPBP1 (or 8 genes including GKAP1 if the proximal breakpoint were centromeric from the segmental duplication), and also the MIR7–1 gene (Fig. 2). The deletion was confirmed using FISH with BAC clone RP11–59M22 (BlueGnome, Cambridge, UK) in the patient but in none of her parents. Subsequent SNP array analysis of the parents confirmed the de novo nature of the deletion and showed its paternal origin. The currently 13-year-old girl was the first child of healthy nonconsanguineous Czech parents aged 29 and 28, both university graduates. The second trimester biochemical screening in pregnancy showed values pointing to an increased risk of chromosome aberrations (AFP 0.89 MoM; uE3 0.68 MoM; HCG 3.16 MoM) but the fetal karyotype from amniotic fluid cells was normal. The girl was delivered at 42 weeks of gestation by Caesarean due to abnormal cardiotocography. The birth parameters were nearly normal: weight of 3,650 g (25th–50th centile), length of 50 cm (25th centile) and head circumference (HC) of 34 cm (
