We characterized three supernumerary marker chromosomes (SMCs) simultaneously present in a 2-year- and 10-month-old male patient with mental retardation and dysmorphic features. Peripheral blood chromosome analysis revealed two to three SMCs in 25/26 cells analyzed. The remaining one cell had one SMC. Microarray comparative genomic hybridization (aCGH) showed mosaicism for gains of 5q35.3, 15q11.2q13.3, and 18p11.21q11.1 regions. All three gains contain multiple OMIM genes. FISH studies indicated that one of the SMCs is a dicentric ring 15 with two copies of the 15q11.2q13.3 region including SNRPN/UBE3A and two copies of the 5q35.3 region. One of the der(18)s contains the 18 centromere and 18p11.2 regions, while the other der(18) has a signal for the 18 centromere only. The phenotype of the patient is compared with that of patients with tetrasomy 15q11.2q13.3, trisomy 5q35.3, and trisomy 18p11.2. Our study demonstrates that aCGH and FISH analyses are powerful tools, which complement the conventional cytogenetic analysis for the identification of SMCs.
Supernumerary marker chromosomes (SMCs) are small extra abnormal chromosomes with an unknown chromosome origin detected by conventional cytogenetic analysis. SMCs are estimated to occur in 0.04%
Molecular cytogenetic techniques including fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY; multicolor banding) have been used as complementary cytogenetic tools to identify the origin of SMCs. Although SKY using 24 chromosome-specific paint probes can be used for identification of chromosomal origin of an SMC, it is unable to precisely identify the DNA components of the SMC [
The patient is a 2-year- and 10-month-old African-American boy. He was born at 42 weeks of gestation to a 16-year-old healthy primigravida via vaginal delivery. The pregnancy was complicated by preeclampsia. His birth weight was 7 pounds and 15 ounces, and his birth length was 21 inches. Neonatal history was unremarkable. He walked at 15 months, but his language development was severely delayed. At age of 2 years and 8 months, he used 12–15 single words. He was also hyperactive.
On his most recent examination at 2 years and 8 months, his height and weight were at the 75th to 95th percentile. His head circumference was at the 25th to 50th percentile. There was a mottled hypopigmentation of the skin but no whorl-shaped lesions or marble cake appearance on his skin. He had plagiocephaly with a prominent forehead and slight flattening of his occiput. His ears were borderline low set with slight posterior rotation, pointed helices, and thick cartilage. There was a small sinus dimple on the root of the helix of the right ear. He had a thin upper lip with long philtrum at 1.8 cm in length and a prominent nasal root. He also had wide-spaced nipples with an internipple distance of 13.5 cm (75th to 97th percentile). His hands measured 10 cm bilaterally (3rd to 25th percentile), and the length of his third finger was 4.3 cm bilaterally (25th percentile). He had mild syndactyly of the second and third toes.
The proband’s mother required an individualized education program (IEP) when she was in school. One 8-year-old cousin, a daughter of a 23-year-old maternal aunt, has developmental delay, and another 6-year-old cousin, a daughter of a 25-year-old maternal aunt, has dyslexia. His 21-year-old maternal uncle also required an IEP in school. The paternal information was not available.
High-resolution chromosome analysis was performed on the peripheral blood specimen using standard cytogenetics protocols. Array-CGH was performed at Signature Genomic Laboratories (Spokane, WA) as described elsewhere [
Cytogenetic analysis of PHA-stimulated peripheral blood lymphocytes revealed a 48,XY,+2mar
G-banded metaphase spread showing three SMCs.
aCGH showing (a) a mosaic gain of the 5q35.3 region, (b) a mosaic gain of the 15q11.2q13.3 region, and (c) a mosaic gain of the 18p11.21q11.1 region.
(a) FISH showing the ring chromosome containing two signals for the RP11-305G6 (green, 5q35.3) and two signals for RP11-1122J3 (red, 15q11.2); (b) FISH showing one der(18) with signal for D18Z1 (green) only and another der(18) with one signal for D18Z1 (green) and for RP11-703l16 (red, 18p11.2).
To estimate the levels of the mosaicism for each marker one hundred interphase cells were counted for each set of probes. The analysis revealed 20.2% interphase cells with r(15), 50.5% interphase cells with both der(18)s, 29.7% interphase cells with the der(18) containing centromere and 18p11.2 region, and 16.8% interphase cells with the der(18) containing 18 centromeric region only. Only three percent of cells analyzed showed a normal hybridization pattern for the chromosome 18CEP and 18p probes.
Maternal peripheral blood chromosome analysis is normal 46,XX in all cells studied. Paternal peripheral blood sample was not available for current study.
In recent years, aCGH has been increasingly utilized for genetic testing of individuals with idiopathic mental retardation, developmental delay, autism spectrum disorders, and multiple congenital anomalies. By combining the aCGH technique with the classical cytogenetic and FISH analyses, we are able to identify cryptic genomic alterations and to further analyze gross genomic alterations identified by the classical cytogenetic analysis. Individual segmental trisomies or tetrasomies 5q35.3, 15q112q13.3, and 18p11.2 resulting from an SMC were reported in patients with varying degrees of mental retardation [
The tetrasomic region of 15q11.2q13.3 detected in our patient contains 26 OMIM genes (
Increase in copies of the genes in this region can occur as a result of interstitial duplications and triplications or as a result of SMCs [
In addition to the parental origin, the dosage of the Prader Willi/Angelman critical region (PWACR) is a major factor contributing to the clinical severity [
Although our patient has a tetrasomy for the 15q11.2q13.3 region, only a few mild phenotypic features associated with duplication or triplication of 15q11.13 are present in our patient, including delayed development, speech delay, hyperactivity, and downslanted palpebral fissures. The mild phenotype may be due to the mosaicism. We were unable to determine the parental origin of the ring 15.
The copy number gain of the 5q35.3 region in our patient contains 8 OMIM genes (
Phenotypic comparison of the reported cases (mosaic or nonmosaic pure partial trisomy 5q35.3) with the present patient.
Authors | Hunter et al. [ | Chen et al. [ | Present | |||
Patient IV. 11 | Patient IV. 5 | Patient V. 13 | Patient V. 14 | |||
Duplication | q35qter | q35qter | q35qter | q35qter | q35.2q35.3 | q35.3q35.3 |
Origin of duplication | t(5;13)(q35;p11.2) | t(5;13)(q35;p11.2) | t(5;13)(q35;p11.2) | t(5;13)(q35;p11.2) | dir dup | Marker |
Birth weight (g) | NA | NA | 3,230 | 2,325 | 2,100 | 3,500 |
Sex | M | F | F | F | F | M |
Age at examination | 31 y and 57 y | 42 y and 68 y | 3 y and 29 y | 6.5 y and 31 y | 11 y | 2 y 10 M |
Growth retardation | + | + | + | + | + | − |
Mental retardation | + | + | + | + | + | + |
Motor retardation | NA | NA | NA | NA | + | + |
Speech retardation | + | |||||
Microcephaly | + | + | + | + | + | Plagiocephaly |
Antimongoloid slant | − | − | − | − | + | − |
Strabismus | − | − | − | − | + | − |
Thin upper lip | + | + | + | + | + | + |
Downturned mouth | + | + | + | + | + | |
Ear anomaly | − | − | − | − | − | + |
Brachydactyly | + | + | + | + | + | |
Syndactyly | + (toe) | |||||
Congenital heart defects | + | − | − | + | − | |
Others | Craniosynostosis | Inguinal hernias |
Trisomy 18p has been reported in the literature. Most of the cases are due to unbalanced translocation [
Because of the simultaneous presence of three marker chromosomes, our patient has segmental tetrasomies of 5q35.3 and 15q11.2q13.3 and a segmental trisomy of 18p11.2 in a mosaic status. He has clinical features of each of the three syndromes. The mottled hypopigmentation observed on the patient’s skin may be associated with the chromosome mosaicism. However, the skin biopsy on the area with hypopigmentation was not performed. This is the first case report which characterizes the origin and gene content of three distinct SMCs derived from three different chromosomes presenting in a mosaic status in a patient with developmental delay, mental retardation, and dysmorphic features. Understanding the origin of the SMC and the gain or loss of genes in any given chromosome abnormality is an important step to predicting the phenotypic outcome of an identified abnormality. This study demonstrated that the aCGH technique in combination with FISH analysis is a powerful tool to identify the origin of SMC.