Chromosomal microarray analysis was performed on amniotic fluid from a 32-year-old woman at 14 weeks gestation. A 6.2 megabase deletion from 15q11.2 to 15q13.1 was identified, consistent with results from a cell-free DNA prenatal screen. This heterozygous deletion was confirmed by fluorescent in situ hybridization.
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This data confirms the presence of a pathogenic heterozygous deletion on chromosome 15q in the fetal DNA that is associated with two disparate genetic diseases (Prader-Willi syndrome and Angelman syndrome). Methylation testing is recommended to determine which disease is affecting the fetus.
The recurrent deletion that impacts chromosome 15q11.2 to 15q13.1 has been well established as pathogenic for either Prader-Willi syndrome (PWS) or Angelman syndrome (AS). The explanation for how a deletion of the same region can be associated with two disparate genetic disorders lies in an epigenetic phenomenon known as imprinting. Imprinting is the selective silencing of genes depending on their parental origin and can be achieved by methylation of the DNA in the vicinity of the gene. Genes in this region of chromosome 15q are known to be biallelic (expressed on both alleles); only paternally expressed (maternally imprinted); or only maternally expressed (paternally imprinted). If the paternal allele is deleted, the paternally expressed genes will not be activated and the resulting phenotype is PWS. If the maternal allele is deleted, the maternally expressed genes will not be activated and the resulting phenotype is AS.
Deletion of this region is typically sporadic in the affected individual and is the mechanism that underlies 70% of individuals with PWS (deletion of paternal allele) and 70% of individuals with AS (deletion of the maternal allele). Once a deletion of this region has been detected, the parent-of-origin can be determined by looking at known methylation sites to determine levels of methylation in the patient as compared to what would be expected if both the maternal and paternal allele are present. This will allow for the dissection of the phenotype, and in this case, could lead to in utero diagnosis of the fetus with either PWS or AS.
Jeanne Theis, Ph.D.
Fellow, Laboratory Genetics and Genomics
Nicole Lynn Hoppman, Ph.D.
Consultant, Laboratory Genetics and Genomics
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science