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
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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
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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)