Concurrent triplication and uniparental isodisomy: evidence for microhomology-mediated break-induced replication model for genomic rearrangements.
Whole-genome oligonucleotide single-nucleotide polymorphism (oligo-SNP) arrays enable simultaneous interrogation of copy number variations (CNVs), copy neutral regions of homozygosity (ROH) and uniparental disomy (UPD). Structural variation in the human genome contributes significantly to genetic variation, and often has deleterious effects leading to disease causation. Co-occurrence of CNV and regions of allelic homozygosity in tandem involving the same chromosomal arm are extremely rare. Replication-based mechanisms such as microhomology-mediated break-induced replication (MMBIR) are recent models predicted to induce structural rearrangements and gene dosage aberrations; however, supportive evidence in humans for one-ended DNA break repair coupled with MMBIR giving rise to interstitial copy number gains and distal loss of heterozygosity has not been documented. We report on the identification and characterization of two cases with interstitial triplication followed by uniparental isodisomy (isoUPD) for remainder of the chromosomal arm. Case 1 has a triplication at 9q21.11-q21.33 and segmental paternal isoUPD for 9q21.33-qter, and presented with citrullinemia with a homozygous mutation in the argininosuccinate synthetase gene (ASS1 at 9q34.1). Case 2 has a triplication at 22q12.1-q12.2 and segmental maternal isoUPD 22q12.2-qter, and presented with hearing loss, mild dysmorphic features and bilateral iris coloboma. Interstitial triplication coupled with distal segmental isoUPD is a novel finding that provides human evidence for one-ended DNA break and replication-mediated repair. Both copy number gains and isoUPD may contribute to the phenotype. Significantly, these cases represent the first detailed genomic analysis that provides support for a MMBIR mechanism inducing copy number gains and segmental isoUPD in tandem.
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Trilochan
T
Sahoo
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Jia-Chi
JC
Wang
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Mohamed M
MM
Elnaggar
Children's Hospital Los Angeles, Division of Medical Genetics, Los Angeles, CA, USA.
Pedro
P
Sanchez-Lara
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Leslie P
LP
Ross
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Loretta W
LW
Mahon
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Katayoun
K
Hafezi
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Abigail
A
Deming
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Lynne
L
Hinman
White Memorial Medical Center, Los Angeles, CA, USA.
Yovana
Y
Bruno
Children's Hospital Los Angeles, Division of Medical Genetics, Los Angeles, CA, USA.
James A
JA
Bartley
Institut für Humangenetik, Jena, Germany.
Thomas
T
Liehr
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
Arturo
A
Anguiano
1] Rady Children's Hospital, Division of Genetics/Dysmorphology, San Diego, CA, USA [2] University of California, San Diego, CA, USA.
Marilyn
M
Jones
D002675:Child, Preschool; D002871:Chromosome Banding; D002892:Chromosomes, Human, Pair 22; D002899:Chromosomes, Human, Pair 9; D003241:Consanguinity; D053960:DNA Breaks; D056915:DNA Copy Number Variations; D005260:Female; D015321:Gene Rearrangement; D005838:Genotype; D059765:Homologous Recombination; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D024182:Uniparental Disomy / Q000175:diagnosis* / Q000235:genetics*