Abstract
BackgroundIntrachromosomal 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.MethodsHere, 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.ResultsWe 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.ConclusionsThese 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.
Highlights
Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation
Carvalho et al Genome Medicine (2019) 11:25 (Continued from previous page). These data provide experimental evidence that, in humans, triplication can lead to segmental uniparental isodisomy (UPD) and imprinting disease
Genotype-phenotype correlations suggest that clinical abnormalities result from gene dosage and expression alterations of genes included within the copy-number gain interval(s) [24] and from unmasking of biallelic autosomal recessive (AR) disease traits; as an example of the latter, Sahoo and colleagues reported a patient with autosomal recessive citrullinemia (MIM#215700) in whom a paternal UPD segment included a paternally inherited pathogenic variant in ASS1 [23]
Summary
Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. 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. Genotype-phenotype correlations suggest that clinical abnormalities result from gene dosage and expression alterations of genes included within the copy-number gain interval(s) [24] and from unmasking of biallelic autosomal recessive (AR) disease traits; as an example of the latter, Sahoo and colleagues reported a patient with autosomal recessive citrullinemia (MIM#215700) in whom a paternal UPD segment included a paternally inherited pathogenic variant in ASS1 [23]. Some of the subjects with TRP/AOH may present clinical phenotypes due to the inheritance of an imprinted locus within the segmental UPD, which was predicted based on the underlying formation mechanism but not yet reported in patients with genomic disorders [25]
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