Enrichment of small pathogenic deletions at chromosome 9p24.3 and 9q34.3 involving DOCK8, KANK1, EHMT1 genes identified by using high-resolution oligonucleotide-single nucleotide polymorphism array analysis

Molecular Cytogenetics, Nov 2016

Background High-resolution oligo-SNP array allowed the identification of extremely small pathogenic deletions at numerous clinically relevant regions. In our clinical practice, we found that small pathogenic deletions were frequently encountered at chromosome 9p and 9q terminal regions. Results A review of 531 cases with reportable copy number changes on chromosome 9 revealed142 pathogenic copy number variants (CNVs): 104 losses, 31 gains, 7 complex chromosomal rearrangements. Of 104 pathogenic losses, 57 were less than 1 Mb in size, enriched at 9p24.3 and 9q34.3 regions, involving the DOCK8, KANK1, EHMT1 genes. The remaining 47 cases were due to interstitial or terminal deletions larger than 1 Mb or unbalanced translocations. The small pathogenic deletions of DOCK8, KANK1 and EHMT1 genes were more prevalent than small pathogenic deletions of NRXN1, DMD, SHANK3 genes and were only second to the 16p11.2 deletion syndrome, 593-kb (OMIM #611913). Conclusions This study corroborated comprehensive genotype-phenotype large scale studies at 9p24.3 and 9q24.3 regions for a better understanding of the pathogenicity caused by haploinsufficiency of the DOCK8, KANK1 and EHMT1 genes. Trial registration number None; it is not a clinical trial, and the cases were retrospectively collected and analyzed.

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Enrichment of small pathogenic deletions at chromosome 9p24.3 and 9q34.3 involving DOCK8, KANK1, EHMT1 genes identified by using high-resolution oligonucleotide-single nucleotide polymorphism array analysis

Wang et al. Molecular Cytogenetics Enrichment of small pathogenic deletions at chromosome 9p24.3 and 9q34.3 involving DOCK8, KANK1, EHMT1 genes identified by using high-resolution oligonucleotide-single nucleotide polymorphism array analysis Jia-Chi Wang Loretta W. Mahon Leslie P. Ross Arturo Anguiano Renius Owen Fatih Z. Boyar Background: High-resolution oligo-SNP array allowed the identification of extremely small pathogenic deletions at numerous clinically relevant regions. In our clinical practice, we found that small pathogenic deletions were frequently encountered at chromosome 9p and 9q terminal regions. Results: A review of 531 cases with reportable copy number changes on chromosome 9 revealed142 pathogenic copy number variants (CNVs): 104 losses, 31 gains, 7 complex chromosomal rearrangements. Of 104 pathogenic losses, 57 were less than 1 Mb in size, enriched at 9p24.3 and 9q34.3 regions, involving the DOCK8, KANK1, EHMT1 genes. The remaining 47 cases were due to interstitial or terminal deletions larger than 1 Mb or unbalanced translocations. The small pathogenic deletions of DOCK8, KANK1 and EHMT1 genes were more prevalent than small pathogenic deletions of NRXN1, DMD, SHANK3 genes and were only second to the 16p11.2 deletion syndrome, 593-kb (OMIM #611913). Conclusions: This study corroborated comprehensive genotype-phenotype large scale studies at 9p24.3 and 9q24.3 regions for a better understanding of the pathogenicity caused by haploinsufficiency of the DOCK8, KANK1 and EHMT1 genes. Trial registration number: None; it is not a clinical trial, and the cases were retrospectively collected and analyzed. Small pathogenic deletions; High resolution oligonucleotide-single nucleotide polymorphism array analysis; Haploinsufficiency; Homozygous deletions - Background Chromosomal microarray analysis (CMA) has been widely utilized for the genome-wide screening of microdeletion and microduplication syndromes [1]. The sizes of well-known microdeletion and microduplication syndromes were usually larger than 1 Mb, such as 1.4 Mb for Williams-Beuren syndrome (OMIM #194050) or 2.8 Mb for DiGeorge syndrome (OMIM #188400). Small (<1 Mb) pathogenic deletions at regions which were not well characterized were frequently encountered during our daily clinical practice, for instance, the chromosomal regions at 9p24.3 and 9q34.3. High-resolution oligo-SNP array is able to reveal a variety of chromosomal disorders including uniparental disomy or extremely small pathogenic deletions which would be missed by low-resolution oligonucleotide CMA. Our and other previous studies showed the cases with uniparental disomy were relatively limited in number on chromosome 9 as compared to chromosome 15, 11 and 7 [2, 3]. In contrast, small pathogenic deletions © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. were frequently encountered at chromosome 9p24.3 and 9q34.3 by using high-resolution oligo-SNP array in postnatal studies. Research endeavors have been significantly prioritized to specific genes such as NRXN1 and SHANK3 in the past [4, 5]. To the best of our knowledge, only four cases with small deletions of 192 kb, 225 kb, 465 kb and 518 kb in size at 9p24.3 involving the DOCK8 and/or KANK1 gene [6–8], and a case of 40 kb deletion in the EHMT1 gene at 9q34.3 [9] have been documented. The purpose of this study is to evaluate 1): the incidence of small (< 1 Mb) pathogenic deletions in postnatal specimens, 2): whether the small pathogenic deletions at 9p24.3 and 9q34.3 constituted a significant proportion of small deletions, 3): what proportion of deletions on chromosome 9 was caused by small pathogenic deletions at 9p24.3 and 9q34.3, 4): the efficacy of identifying extremely small homozygous pathogenic deletions using high-resolution oligo-SNP array. Results The incidence of small pathogenic deletions in postnatal specimens studied by high-resolution oligo-SNP array Approximately 38,000 postnatal specimens were studied by high-resolution oligo-SNP array in our laboratory from 2011 through 2015. Of these, we reported approximately 13,000 (34 %) pathogenic variants or variants of uncertain clinical significance (VOUS). The detection rate was consistent with our previous study [2]. Of the 13,000 variants, a total of 373 recurrent (at least 3 cases) small pathogenic losses were identified (Fig. 1). The 16p11.2 deletion syndrome, 593-kb (OMIM #611913) is the most common sma (...truncated)


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Jia-Chi Wang, Loretta Mahon, Leslie Ross, Arturo Anguiano, Renius Owen, Fatih Boyar. Enrichment of small pathogenic deletions at chromosome 9p24.3 and 9q34.3 involving DOCK8, KANK1, EHMT1 genes identified by using high-resolution oligonucleotide-single nucleotide polymorphism array analysis, Molecular Cytogenetics, 2016, pp. 82, 9, DOI: 10.1186/s13039-016-0291-3