Small supernumerary marker chromosomes (SMCs): genotype-phenotype correlation and classification

Abstract

Small supernumerary marker chromosomes (SMCs) are present in about 0.05% of the human population. In approximately 30% of SMC carriers (excluding the approximately 60% SMC derived from one of the acrocentric chromosomes), an abnormal phenotype is observed. The clinical outcome of an SMC is difficult to predict as they can have different phenotypic consequences because of (1). differences in euchromatic DNA-content, (2). different degrees of mosaicism, and/or (3). uniparental disomy (UPD) of the chromosomes homologous to the SMC. Here, we present 35 SMCs, which are derived from all human chromosomes, apart from chromosome 6, as demonstrated by the appropriate molecular cytogenetic approaches, such as centromere-specific multicolor fluoresence in situ hybridization (cenM-FISH), multicolor banding (MCB), and subcentromere-specific multicolor FISH (subcenM-FISH). In nine cases without an aberrant phenotype, neither partial proximal trisomies nor UPD could be detected. Abnormal clinical findings, such as psychomotoric retardation and/or craniofacial dysmorphisms, were associated with seven of the cases in which subcentromeric single-copy probes were proven to be present in three copies. Conversely, in eight cases with a normal phenotype, proximal euchromatic material was detected as partial trisomy. UPD was studied in 12 cases and subsequently detected in two of the cases with SMC (partial UPD 4p and maternal UPD 22 in a der(22)-syndrome patient), indicating that SMC carriers have an enhanced risk for UPD. At present, small proximal trisomies of 1p, 1q, 2p, 6p, 6q, 7q, 9p, and 12q seem to lead to clinical manifestations, whereas partial proximal trisomies of 2q, 3p, 3q, 5q, 7p, 8p, 17p, and 18p may not be associated with significant clinical symptoms. With respect to clinical outcome, a classification of SMCs is proposed that considers molecular genetic and molecular cytogenetic characteristics as demonstrated by presently available methods.

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).…”

“…These chromosomes are detected in 0.04% of newborn children, whereas in developmentally retarded patients the rate is 0.22% (1)(2)(3). sSMCs are also present in 0.08% of unselected pre-natal cases and in 0.20% of pre-natal cases with ultrasound abnormalities (2).…”

Forty-two supernumerary marker chromosomes (SMCs) in 43 273 prenatal samples: chromosomal distribution, clinical findings, and UPD studies

“…Apart from the detailed review of Crolla, 10 so far only one large-scale study of the euchromatic DNA content in pre-and postnatal SMCs has been reported. 7 Frequencies of the different SMCs Our study shows a prevalence of 1/1032 (n ¼ 42) for SMCs at prenatal diagnosis, 1/1492 for de novo SMCs (n ¼ 29), and 1/3328 for the familial SMCs (n ¼ 13). Previous studies reported SMC frequencies of 0.4/1000, 3 0.8/1000, 21 1/1000, 5 and 1.5/1000.…”

“…7,11,17 The stepwise investigation of minute SMCs (classes III and IV) included (i) the identification of the a-satellite suprachromosomal family by low-stringency hybridization allowing cross-hybridization between members of the same suprafamily, 13 (ii) the identification of the chromosomal origin by highstringency (chromosome-specific) hybridization of alphoid DNA probes, and (iii) analysis of the euchromatin DNA content using region-specific probes such as BACs. 7,11 There have been attempts to detect the euchromatin on SMCs by using of whole chromosome painting, 16 but due to the presence of centromeric DNA in some paints, this approach is artifact prone: heterochromatic and euchromatic SMCs (classes I vs II or classes III vs IV) may be confused. This study has shown that the stepwise procedure is effective and fast; final results were obtained (usually within 1 week) for 92.3% (12 of 13) of the minute SMCs.…”

“…4 -8 Although most cases have been characterized by standard FISH, special techniques such as chromosomal microdissection, 9 subcentromere-specific multifluor FISH (subcenM-FISH), and multicolor banding (MCB) have been applied to exceptional cases. 7 Occasionally, SMCs lead to spontaneous abortions. Specific SMCs have been associated with Pallister -Killian syndrome (Online Mendelian Inheritance in Man (OMIM) 601803), inverted duplication 15q12 -q13 syndrome, isochromosome 18p syndrome, and cat eye syndrome (CES) (OMIM 115470).…”