Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

Gu, Shen; Posey, Jennifer E.; Yuan, Bo; Carvalho, Cláudia; Luk, Ho‐Ming; Erikson, Kelly; Lo, Ivan F.M.; Leung, Gordon K. C.; Pickering, Curtis R.; Chung, Brian Hon‐Yin; Lupski, James R.

doi:10.1002/humu.22929

Cited by 16 publications

(19 citation statements)

References 20 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, droplet digital PCR (ddPCR) can further distinguish amplification and copy number gains beyond duplication [e.g. triplication, quadruplication(Gu et al 2016)]. Moreover, based on the advances in SNP calling from next-generation sequencing data (Nielsen et al 2011), CNVs can easily be detected by particular algorithms with an adequate read depth (Goodwin et al 2016; Hormozdiari et al 2009; Iossifov et al 2014).…”

Section: Discussionmentioning

confidence: 99%

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

et al. 2018

Self Cite

View full text Add to dashboard Cite

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the misannotation of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS that may result due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model including mostly one rare variant deletion CNV allele and one common variant noncoding hypomorphic haplotype of the TBX6 gene. We demonstrate that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study that can be ‘induced’ by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p<1×10−6 and p=0.034, respectively), indicating that such locus co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We propose that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits may improve genetic model analyses and better integrate. GWAS with robust Mendelian principles

show abstract

Section: Discussionmentioning

confidence: 99%

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…They can be formed in a single mutational event during DNA repair by iterative template switching within stretches of microhomology . Additionally, CGRs may expand, that is, triplication‐normal‐triplication pattern to quadruplication‐normal‐quadruplication pattern . CGRs, in particular triplications, can be associated with extended regions of segmental copy‐number‐neutral absence of heterozygosity (AOH) or regional uniparental disomy (UPD).…”

Section: Upstream Mechanisms: Genomic Instability Predisposes To Genomentioning

confidence: 99%

“…34,45 Additionally, CGRs may expand, that is, triplication-normal-triplication pattern to quadruplication-normal-quadruplication pattern. 46 CGRs, in particular triplications, can be associated with extended regions of segmental copy-number-neutral absence of heterozygosity (AOH) or regional uniparental disomy (UPD). Template switches between homologs vs sister chromatids, during repair of double-stranded DNA breaks or during mitotic crossing-over, have been implicated in such rearrangements.…”

Section: Complex Rearrangementsmentioning

confidence: 99%

Genomic disorders 20 years on—mechanisms for clinical manifestations

2017

View full text Add to dashboard Cite

Genomic disorders result from copy-number variants (CNVs) or submicroscopic rearrangements of the genome rather than from single nucleotide variants (SNVs). Diverse technologies, including array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) microarrays, and more recently, whole genome sequencing and whole-exome sequencing, have enabled robust genome-wide unbiased detection of CNVs in affected individuals and in reportedly healthy controls. Sequencing of breakpoint junctions has allowed for elucidation of upstream mechanisms leading to genomic instability and resultant structural variation, whereas studies of the association between CNVs and specific diseases or susceptibility to morbid traits have enhanced our understanding of the downstream effects. In this review, we discuss the hallmarks of genomic disorders as they were defined during the first decade of the field, including genomic instability and the mechanism for rearrangement defined as nonallelic homologous recombination (NAHR); recurrent vs nonrecurrent rearrangements; and gene dosage sensitivity. Moreover, we highlight the exciting advances of the second decade of this field, including a deeper understanding of genomic instability and the mechanisms underlying complex rearrangements, mechanisms for constitutional and somatic chromosomal rearrangements, structural intra-species polymorphisms and susceptibility to NAHR, the role of CNVs in the context of genome-wide copy number and single nucleotide variation, and the contribution of noncoding CNVs to human disease.

show abstract

“…The number of positive and negative droplets that contain a target template is used to calculate the concentration of the target and reference DNA sequences and their Poisson-based 95% confidence interval (Hindson, et al 2011). The ddPCR methodology can readily distinguish duplication, triplication and even quadruplication of a locus (Gu, et al 2016). …”

Section: Methodsmentioning

confidence: 99%

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects

Daly¹,

Yuan²,

Fina³

et al. 2016

Endocrine-Related Cancer

Self Cite

View full text Add to dashboard Cite

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101. We studied XLAG syndrome patients (N=18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome were identified with Xq26.3 duplications using high definition array comparative genome hybridization (HD-aCGH). We noted males with XLAG had a decreased log2 ratio compared with expected values, suggesting potential mosaicism, while females showed no such decrease. As compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1-53.8%. These characteristics were replicated using a novel, personalized breakpoint-junction specific quantification droplet digital PCR (ddPCR) technique. Using a separate ddPCR technique we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism and identified one female gigantism patient that had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

show abstract

Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

Cited by 16 publications

References 20 publications

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

Genomic disorders 20 years on—mechanisms for clinical manifestations

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects

Contact Info

Product

Resources

About