A Complex Structural Rearrangement Resulting in Recurrent SCN1A Deletion Identified by Optical Genome Mapping
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction
Balanced and complex structural variants can be difficult to detect and characterize using traditional clinical methodologies, such as karyotyping, microarray, and short read next-generation sequencing.
Case Presentation
We present a family with multiple individuals affected with Dravet syndrome, a severe, early-onset genetic epilepsy, with a heterozygous deletion of the SCN1A gene. Despite the recurrent nature of the deletion within the family, parental testing for two of the probands did not detect the deletion in any of the parents, raising suspicion for a balanced rearrangement.
Diagnostic Workup
Optical genome mapping (OGM) was performed on high molecular weight DNA extracted from whole blood from one of the deletion-negative parents who was suspected to be an obligate carrier based on the pedigree. The analysis detected a complex balanced rearrangement involving insertion of material from 2q24.3 (containing the SCN1A gene) into a region of chromosome 18 (q22.1-q23) that was also inverted. OGM analysis of 4 additional family members was performed. The balanced rearrangement was identified in 2 other deletion-negative individuals with affected children. Two individuals with Dravet syndrome, known to carry the SCN1A deletion by panel testing, were found to only have the recombinant chromosome 2 with the approximately 525-kb deletion of 2q24.3.
Treatment and Management
The family was counseled about the complex rearrangement and how it relates to the pathogenic 2q24.3 deletion detected in multiple affected family members. Additionally, the family was counseled about the risk for balanced carriers to have children with unbalanced chromosomal complements, including not only rearrangements causing SCN1A-related conditions but other conditions as well. Testing for additional family members by OGM was recommended to determine carrier status.
Outcome and Follow-Up
Following identification of the complex rearrangement, additional family members were referred to genetics for testing by OGM.
Discussion
The balanced rearrangement identified in this family is unique and was not detected by previous targeted testing methods; however, the recurrence risk for the 2q24.3 deletion is significant for the balanced carriers of this complex rearrangement. One other insertional translocation involving the SCN1A gene has been described; however, the alteration was de novo in that case rather than the result of an inherited rearrangement.
Conclusion
OGM is an emerging technology for the detection and characterization of complex structural variants and should be considered in cases with a suspected genomic rearrangement not detectable by other clinical methodologies.
Balanced and complex structural variants can be difficult to detect and characterize using traditional clinical methodologies, such as karyotyping, microarray, and short read next-generation sequencing.
Case Presentation
We present a family with multiple individuals affected with Dravet syndrome, a severe, early-onset genetic epilepsy, with a heterozygous deletion of the SCN1A gene. Despite the recurrent nature of the deletion within the family, parental testing for two of the probands did not detect the deletion in any of the parents, raising suspicion for a balanced rearrangement.
Diagnostic Workup
Optical genome mapping (OGM) was performed on high molecular weight DNA extracted from whole blood from one of the deletion-negative parents who was suspected to be an obligate carrier based on the pedigree. The analysis detected a complex balanced rearrangement involving insertion of material from 2q24.3 (containing the SCN1A gene) into a region of chromosome 18 (q22.1-q23) that was also inverted. OGM analysis of 4 additional family members was performed. The balanced rearrangement was identified in 2 other deletion-negative individuals with affected children. Two individuals with Dravet syndrome, known to carry the SCN1A deletion by panel testing, were found to only have the recombinant chromosome 2 with the approximately 525-kb deletion of 2q24.3.
Treatment and Management
The family was counseled about the complex rearrangement and how it relates to the pathogenic 2q24.3 deletion detected in multiple affected family members. Additionally, the family was counseled about the risk for balanced carriers to have children with unbalanced chromosomal complements, including not only rearrangements causing SCN1A-related conditions but other conditions as well. Testing for additional family members by OGM was recommended to determine carrier status.
Outcome and Follow-Up
Following identification of the complex rearrangement, additional family members were referred to genetics for testing by OGM.
Discussion
The balanced rearrangement identified in this family is unique and was not detected by previous targeted testing methods; however, the recurrence risk for the 2q24.3 deletion is significant for the balanced carriers of this complex rearrangement. One other insertional translocation involving the SCN1A gene has been described; however, the alteration was de novo in that case rather than the result of an inherited rearrangement.
Conclusion
OGM is an emerging technology for the detection and characterization of complex structural variants and should be considered in cases with a suspected genomic rearrangement not detectable by other clinical methodologies.