Skip to main content

Conference Program

Subpage Hero

Loading

Unbalanced three-way translocation identified in a patient with developmental delay using chromosomal microarray analysis and karyotyping

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction
Chromosomal microarray analysis (CMA) can reliably detect cytogenetically visible and submicroscopic copy number variants (CNVs) as well as unbalanced complex chromosome rearrangements (CCRs) at a resolution higher than karyotyping and fluorescence in situ hybridization (FISH). However, to identify balanced rearrangements which cannot be detected by CMA, determine the structure of abnormal chromosome(s), or clarify the mechanism underlying the abnormal findings on CMA for informed clinical management, additional testing following CMA is required.

Case Presentation
A 2-year-old male with failure to thrive, macrocephaly, developmental delay and autism was referred to the Stanford Cytogenetics Laboratory for CMA. The proband was born at term and was admitted to the NICU for low birth weight, abnormal breathing and poor feeding. He is the first child of healthy, non-consanguineous parents with no family history of chromosomal abnormalities, genetic conditions, or known exposure to drugs or radiation. Previous biochemical screening tests were not suggestive of a metabolic disorder. Solo exome sequencing was non-diagnostic but identified a CNV on chromosome 1q41 with unclear breakpoints.

Diagnostic Workup
CMA identified a heterozygous 2.67 Mb loss at 1q41, clarifying the breakpoints of the chromosome 1 CNV reported on exome. Two additional heterozygous CNVs, a 975 kb loss at 4p14 and a 147 kb loss at 7p21.2, were identified by CMA. Parental CMA testing showed normal results, suggesting a de novo occurrence of all three CNVs and the possibility of a CCR in the proband. Follow-up chromosome analysis showed a karyotype with a three-way translocation involving chromosomes 1, 4, and 7, as well as a supernumerary marker chromosome, 47,XY,t(1;7;4)(q41;p21.2;p14),+mar. Thus, the translocation breakpoints detected by karyotyping correspond to the copy number variants detected by CMA. Analysis of SNP patterns in the proband and both parents revealed a paternal origin of this CCR.

Discussion
Constitutional CCRs involving multiple breaks and exchanges of chromosomal segments on more than two chromosomes are extremely rare in humans. Each CCR is a unique aberration, and its phenotypic consequences are determined by the chromosomes involved, the parent of origin and gene position effect impacted by the rearrangement. Impaired replication, recombination, and double-strand break repair during meiosis, as well as chromothripsis have been proposed as possible causes of CCRs. Application of high-resolution techniques is important in clarifying which genes are affected by the CCR and consequently, whether the CCR will have a pathogenic effect. Due to the complexity and de novo nature of this CCR, the recurrence risk could not be provided to the family, and prenatal counseling in future pregnancies was recommended.

Conclusion
This case report highlights the benefits of familial testing and follow-up studies to further characterize abnormalities seen on chromosomal microarray. The overall presence of the CCR is pathogenic in the setting of a three-way unbalanced chromosomal translocation. While each individual CNV detected by CMA may or may not contribute to the proband’s phenotype, it is important to resolve the mechanism of pathogenesis using additional technologies since it impacts diagnosis, counseling and clinical management of the patient and the family.

Agenda

Sponsors