Mosaicism

• Level I
• Single abnormal cell
• Almost certainly a cultural articfact
• Level II
• More than one abnormal cell within a single vessel
• Risk of mosaicism in the conceptus:
• < 2%
• Up to 20% ?
• Level III
• More than one abnormal cell distributed over 2 or more vessels
• Significant risk of true mosaicism
• For trisomies:
• 50% risk for autosome
• 90% risk for sex chromosome
• 80% risk for ESAC
• Workup:
• Level I mosaicism:
• No further workup (minimum 10 colonies from 2 or more independent cultures)
• Exceptions:
• Marker chromosome
• others
• Level II mosaicism:
• No additional workup required:
• balanced structural rearrangement (single colony)
• break at centromere with loss of one arm (single colony)
• Indications for moderate workup:
• Extra sex chromosome
• Autosomal trisomy involving (1, 2, 3, 4, 6, 7, 10, 11, 17, 19)
• 45,X (multiple cells / single or multiple colonies)
• monosomy (multiple cells)
• Marker chromosome (single cell / colony)
• Balanced structural rearrangement (multiple colonies / multiple cells in flask method)
• Unbalanced structural rearrangement (single colony)
• Indications for an extensive workup:
• Autosomal trisomy involving (2, 5, 8, 9, 12, 13, 14, 15, 16, 18, 20, 21, or 22)
• Unbalanced structural arrangement (multiple colonies / multiple cells in flask method)
• Marker chromosome (multiple colonies / multiple cells in flask method
• Standard ( no additional) workup:
• Flask method: 20 cells (10 from each of two independent cultures)
• In situ method: 15 colonies (from at least two independent vessels)
• Moderate workup:
• Flask method: Examine 20 extra cells from a different flask than which the abnormal cell(s) was found
• In situ method: Examine 12 extra colonies from different vessels
• Extensive workup:
• Flastk method: 40 additional cells (20 from each of 2 flasks)
• In situ method: Examine 24 extra colonies from multiple vessels, not including the initial vessel in which abnormal colony(ies) was found
• Level III mosaicism:
• No additional analysis is necessary
• Clinically suspected mosaicism:
• Count 25 to 50 mets for G-banding
• Mosaicism on FISH
• Analyze 100 to 500 (depending on control values) interphase nuclei
• Reporting:
• Level I:
• Not reported
• Exceptions:
• Level II:
• Usually not reported
• May report “level II mosaicism” or “inconclusive result” for:
• Analysis of a minimum number of additional colonies / metaphases is not possible
• Clinical findings:
• Fetal anomalies
• IUGR
• Suspected vanishing twin on U/S
• Aberrations known to be associated with clinically significant mosaic states
• additional studies may be suggested for those that are reported
• level III:
• all should be reported
• additional studies may be suggested
• fetal U/S
• cytogenetic confirmation of the prenatal diagnosis in all cases
• more than one tissue may be required
• risk of UPD for trisomy 15 mosaicism in CVS or amniotic fluid is estimated at 11-29%

References:

• Gardner RJM, Sutherland GR, eds. Chromosome Abnormalities and Genetic Counseling (1996).
• Hsu LYF, Peter A. Benn. Revised guidelines for the diagnosis of mosaicism in amniocytes. Prenatal Diagnosis. 1999;19(11):1081-1090.
• CCMG Cytogenetic Practice Guidelines for Prenatal Samples, Feb 2010.
• CCMG Cytogenetic Practice Guidelines, 2003.

· CCMG Guidelines: Prenatal and Postnatal Diagnostic Testing for Uniparental Disomy (UPD). Clinical Genetics (in press, 2010).