Trisomy of the short arm of chromosome 12 is a rare chromosomal anomaly with an estimated incidence of 0.2:10,000 births and in the majority of reported cases the trisomy 12p results from malsegregation of a balanced parental translocation.
We report a prenatal diagnosis of a duplication of 12p and a distal 6q deletion by direct FISH on chorionic villi sampling with subtelomeric probes. The mother is a carrier of a balanced reciprocal translocation 46,XX,t(6;12)(q27;p11.21) and her brother died in the neonatal period at the age of 6 weeks of cardio-respiratory failure. He had a duplication of 12p and a terminal 6q deletion as an unbalanced product of the parental translocation and he had facial dysmorphism, a marked flexion deformity of the fingers and toes and a major heart defect.
Trisomy of the short arm of chromosome 12 is a rare chromosomal anomaly with an estimated incidence of 0.2:10,000 births and was first reported by Uchida and Lin .
Approximately 40 patients have been reported and the majority of reported cases resulted from malsegregation of a balanced paternal translocation, and in these cases the clinical findings also reflect monosomy of the other chromosome involved in the original translocation.
In this family a maternal brother died neonatally with a hypoplastic left heart and a trisomy12p/terminal 6q deletion.
Cytogenetic studies and results
Chromosome analysis of the parents on cultured lymphocytes had been done previously and had shown a normal karyotype in the father and a balanced reciprocal translocation 46,XX,t(6;12)(q27;p11.21) in the mother. She had inherited the translocation from her father and in this family her brother died at 6 weeks with a trisomy 12p and a terminal 6q deletion .
In this pregnancy direct FISH analysis with subtelomeric probes 6q and 12p on chorionic villi sampling revealed a trisomy subtelomeric 12p (fig. 1a) and a monosomy subtelomeric 6q (fig. 1b) as an unbalanced product of the maternal translocation.
The karyotype on cultured chorionic villi confirmed the 46,XX,6q+ (fig. 2) as the unbalanced product of the t(6q;12p)mat.
Molecular karyotyping on stocked DNA was performed and shows a duplication of the whole short arm of chromosome 12 and a 4 Mbase deletion of the long arm of chromosome 6 (46,Xy,der(6;12)arr cgh 6q27(RP11-351J23→CTB-57H24)x1 / 12pter11.1(RP11-28313→RP11-460N10)x3.
Figure 1a-b: direct FISH on chorionic villi sampling at 12 weeks with subtelomeric probe for 12p revealing trisomy 12p (fig 1a) and with subtelomeric probe for 6 revealing a monosomy subtelomeric 6q (fig 1b).
Figure 2: The karyotype on cultured chorionic villi confirmed the 46,XX,6q+.
In this family 2 children, a girl and a boy, inherited a balanced reciprocal translocation, t(6q;12p) from their father. Their brother died in the neonatal period at 6 weeks due to cardiorespiratory failure and a trisomy 12p/terminal 6q deletion. This boy had a normal birth weight (3450g, 50th centile), with a head circumference of 33 cm (3rd centile). He had poorly lobulated ears, a flat occiput, a short neck with abundant skin, low implanted nipples, deep skin creases on the palms of his hands and feet, bilateral simian fold, a sandal gap and marked flexion deformity of the hands and feet. He also had a complex cardiac malformation with a double outlet right ventricle with mitral valve atresia.
The girl with the balanced translocation had one early miscarriage and in this pregnancy a chorionic villus sampling was performed at 12 weeks: nuchal translucency was normal and direct FISH and karyotype on cultured villi revealed a trisomy 12p/terminal 6q deletion and therefore the pregnancy was terminated.
Trisomy 12p is a chromosomal disorder with an estimated incidence of 0.2:10,000 births . Approximately 40 patients have been reported and the majority of reported cases resulted from malsegregation of a balanced paternal translocation.
In pure trisomy 12p gross malformations are lacking and it is characterised by mental retardation, heavy birth weight, hypotonia and facial dysmorphism with macrocephaly, short neck, flat face, high forehead, prominent cheeks, large philtrum, short nose with anteverted nostrils and broad everted lower lip . Allen et al. proposed a classification for trisomy 12p from I to V, based on the extent of 12 p trisomy and the presence of other chromosomal aneusomies: category IV involves complete trisomy 12p with monosomy/trisomy of a non-acrocentric chromosome other than 12p. In this category heart defects, renal abnormalities and a sandal gap of toes is commonly seen.
Two other cases of hypoplastic left heart and early death as in the present brother were reported with trisomy 12p and aneusomy of a non–acrocentric chromosome [5, 6].
In this family the translocation involved almost the whole short arm of chromosome 12 (pter-p11.21) and a very small part of the long arm of chromosome 6 (6q27).
6q terminal deletions have been known since 1975 .Only few cases with isolated 6q terminal deletion have been reported, due to the light staining of the 6q telomeric region with G-banding and the lack of an easily recognizable phenotype. Clinical findings commonly seen in 6q terminal deletion syndrome are mental retardation, structural brain anomalies, facial dysmorphism (a long face with large rotated ears) and focal epilepsy .
Congenital heart defects are mostly associated with large cytogenetically visible 6q deletions .
Eash et al. ascertained five patients with 6q subtelomere deletions ranging from <0.5 to 8Mb . They reviewed the defects in patients with cytogenetically visible 6q deletions and subtelomere deletions and found cardiac defects frequently reported in patients with cytogenetically visible 6q26-q27 deletions but no reports of cardiac defects in patients with subtelomere 6q deletions with the exception of dextrocardia in a patient with a de novo 6q27 deletion of 7.5Mbase .
Direct fluorescence in situ hybridisation (FISH) with specific subtelomeric probes allows the rapid prenatal diagnosis of a malsegregation of a balanced maternal translocation, as presented here, with the diagnosis of a trisomy subtelomeric 12p and a monosomy subtelomeric 6q on chorionic villi at 12 weeks as an unbalanced product of a maternal balanced reciprocal translocation. As presented here, the result with direct FISH on chorionic villi is present after 24-48 hours allowing an early pregnancy termination in these at-risk families.
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