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Identification of a balanced rearrangement of 22q11.2 in a family with a history 22q11.2 microduplication and microdeletion syndromes

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction
The majority of 22q11.2 microdeletion syndrome cases are de novo with 5-10% of cases being inherited. 22q11.2 microduplication syndrome is diagnosed less often but is almost always inherited from an asymptomatic or mildly symptomatic parent. Here we report an individual identified with 22q11.2 microdeletion syndrome with a strong family history of 22q11.2 microduplication syndrome and describe inheritance of the deletion from his mother who was determined to be a balanced carrier of both rearrangements.

 

Case Presentation
A 7 month old boy presented to genetics with mild developmental delay, a small patent foramen ovale, subtle dysmorphic features and a strong family history of 22q11.2 microduplication syndrome. Both of his maternal cousins were diagnosed 22q11.2 microduplication syndrome with congenital anomalies requiring surgical repair.

 

Diagnostic Workup
CGH microarray was performed on peripheral blood from the patient and identified the common 2.54 Mb deletion at chromosome band 22q11.2 spanning breakpoints A through D. Subsequent microarray testing of the patient’s mother revealed a normal, two copy state for the 22q11.2 region. Of note, two sisters of the mother were previously tested by CGH microarray and found to carry the 22q11.2 microduplication. FISH testing with the HIRA probe revealed that the mother carried two copies of the locus by interphase FISH analysis but only one signal was visible by metaphase FISH. These results suggested that that one chromosome 22 homologue harbored the 22q11.2 microduplication, and the other homologue was deleted for the 22q11.2 region.

 

Treatment and Management
The proband was referred to the 22q center for a more complete workup to assess for heart anomalies, immune issues, learning, speech delay, and/or behavior difficulties that could be proactively managed. The mother was counselled on the reproductive implications of her balanced chromosomal rearrangement. Since most cases of 22q11.2 deletion are de novo, there is minimal recurrence risk for the parents. However, for inherited cases, the recurrence risk is 50%. This case demonstrates a unique carrier finding, as the mother does not have a normal copy of chromosome 22 resulting in 100% recurrence risk of future children with either 22q11.2 microdeletion syndrome or 22q11.2 microduplication syndrome.

 

Outcome and Follow-Up
The proband was found to have no additional features of 22q11.2 microdeletion syndrome and is making good progress in developing fine and gross motor skills.

 

Discussion
Balanced rearrangements of the 22q11.2 region are rare, and only one case has been previously reported. This case emphasizes the importances of carrying out FISH analyses for cases in which microarray reveals a normal copy number state in parental samples when accompanied by a strong family history of 22q11.2 rearrangements.

 

Conclusion
Balanced rearrangements of the 22q11.2 region are important to identify in order to provide accurate genetic counselling for recurrence risk assessment.

 

 

Agenda

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