Prenatal Diagnosis of Minute Supernumerary Marker Chromosomes

Abstract

The identification of supernumerary marker chromosomes (SMC) at prenatal diagnosis is problematic, particularly for the prediction of phenotype. The assessment of phenotypic risk is based on the size, morphology and origin of the SMC. Fluorescence in situ hybridization (FISH) characterization and family studies are also employed to aid in determining the significance of a prenatally ascertained SMC. Generally, SMC containing euchromatin are more likely to be associated with abnormal phenotypes and SMC without euchromatin are more likely to result in normal phenotypes. The smallest of SMC, minute SMC (minSMC) appear as dot-like or centric fragments and are particularly difficult to identify and characterize. Previous empirical observations suggested that the risk of phenotypic abnormality in prenatally ascertained minSMC was ≤5%. We identified minSMC in chorionic villus samples (CVS) or amniocytes from 11 unrelated pregnancies. The chromosomal origin of each minSMC was identified by sequential FISH analysis with chromosome-specific centromere probes. Further FISH analysis with whole chromosome paint probes was undertaken to assess each minSMC for the presence or absence of euchromatin, since the presence of euchromatin may be associated with a higher risk of abnormality. Two minSMC were shown to have euchromatin. The first, a minSMC(12) was found in CVS but not confirmed in amniocytes, indicating confined placental mosaicism. The second, a minSMC derived from chromosome 19, was associated with ultrasound abnormalities. Apart from a case with mild speech delay, the remaining minSMC cases without detectable euchromatin had a normal outcome at birth and/or on longer term follow-up. Additional FISH analyses with a telomeric repeat probe showed no signal on any of the minSMC tested, suggesting that they were ring chromosomes in structure. These data further support the concept that minSMC containing euchromatin are more likely to be associated with an abnormal phenotype, although as more data are collected, this may vary by chromosome of origin. The absence of detectable euchromatin, while not guaranteeing a normal result, is most likely to have a normal outcome. The present report and previous studies do not yet allow any significant adjustment of the empirical ≤5% risk estimate for minSMC identified at prenatal diagnosis. However, reporting of additional cases with characterization of the minSMC and particularly with long-term follow-up will, in time, allow for more accurate risk estimates and provide prognostic information.

Characterization of 23 small supernumerary marker chromosomes detected at pre-natal diagnosis: The value of fluorescence in situ hybridization

“…The first patient had a ring chromosome containing a small amount of euchromatic material, while the second patient was a carrier of a small metacentric and most probably heterochromatic marker. A similar case was reported by Cotter et al (25), with a karyotype of 47,XY,+mar [3]/46,XY [17] reported to be phenotypically normal at birth. The fourth case of a prenatally detected 46,XY/47,XY,+r(20)/47,XY,+20, showed delayed psychomotor development, physical anomalies and growth retardation at the age of 16 months (26).…”

Supernumerary marker chromosomes derived from chromosome 6: Cytogenetic, molecular cytogenetic, and array CGH characterization

“…Phenotype and development were normal in both patients at the time of follow‐up. These cases are consistent with the observation that minute SMCs with no detectable euchromatin have a low risk of phenotypic abnormality [Cotter et al, 2005]. The 3rd patient reported by Leite et al, [2006] with the SMC(6) containing 6cen→6p12 had a normal phenotype and is also consistent with the genotype–phenotype predictions mentioned above [Liehr et al, 2006a].…”

Multiplex ligation dependent probe amplification (MLPA) for rapid distinction between unique sequence positive and negative marker chromosomes in prenatal diagnosis

“…However, as with array analysis, MLPA will give normal results in case of an unique sequence-negative sSMC or in case of low level mosaicism [16]. Therefore, other techniques such as cenM-FISH [8] or sequential targeted FISH [29], although labour-intensive and frequently time-consuming, will be necessary for determining the chromosomal origin. Since such a sSMC most probably does not contain euchromatin, in the meanwhile, the parents can be karyotyped after reassurance.…”