Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome

Autor: Shalini N. Jhangiani, Chad A. Shaw, Rupa S. Kanchi, Patricia I. Bader, John Beaulaurier, V. Reid Sutton, Pawel Stankiewicz, Bo Yuan, Sissel Juul, James R. Lupski, Eoghan D. Harrington, Richard A. Gibbs, Claudia M.B. Carvalho, Neil A. Hanchard, John W. Belmont, Daniel J. Turner, Hadia Hijazi, Zeynep Coban-Akdemir, Matthew Pendleton, Sau Wai Cheung, Donna M. Muzny
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
DNA Replication
Male
congenital
hereditary
and neonatal diseases and abnormalities
lcsh:QH426-470
Runs of homozygosity (ROH)
lcsh:Medicine
Locus (genetics)
Chromosome Disorders
Runs of Homozygosity
Biology
Gene dosage
Polymorphism
Single Nucleotide
03 medical and health sciences
Genomic Imprinting
Young Adult
0302 clinical medicine
Absence of heterozygosity (AOH)
Triplication
Genetics
Humans
Allele
Molecular Biology
Gene
Genetics (clinical)
Exome sequencing
Chromosome Aberrations
Chromosomes
Human
Pair 14
Research
Inter-homologous chromosomal template switch
lcsh:R
DUP-TRP/INV-DUP
DNA Methylation
MMBIR
Pedigree
lcsh:Genetics
030104 developmental biology
Differentially methylated regions
Phenotype
ES
Uniparental Isodisomy
030220 oncology & carcinogenesis
Replicative-based mechanism
Molecular Medicine
Complex genomic rearrangement
Zdroj: Genome Medicine, Vol 11, Iss 1, Pp 1-14 (2019)
Genome Medicine
DOI: 10.1186/s13073-019-0633-y
Popis: Background Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases. Methods Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology. Results We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay. Conclusions These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases. Electronic supplementary material The online version of this article (10.1186/s13073-019-0633-y) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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