Sara Kaffe

Paternal uniparental disomy for chromosome 14 : a case report and review

Uniparental disomy (UPD) for several chromosomes has been associated with disease phenotypes. Maternal UPD for chromosome 14 has been described and has a characteristic abnormal phenotype. Paternal UPD14 is rare and only three previous cases have been reported. We describe a new case of paternal UPD for chromosome 14 in an infant with a 45,XX,der(13q;14q) karyotype, which was confirmed by molecular analysis. The proposita had findings similar to those of the previous cases of patUPD14 and we conclude that there is a characteristic patUPD14 syndrome most likely due to imprinting effects. Couples with Robertsonian translocations involving chromosome 14 should be counseled as to the possibility of UPD14 and the option of prenatal diagnosis when indicated.

Clinical applications of comparative genomic hybridization.

Purpose: Comparative genomic hybridization (CGH) is a powerful DNA-based cytogenetic technique that allows the entire genome to be scanned for chromosomal imbalances without requiring the sample material to be mitotically active. During the past 2 years we received many requests from various medical centers around the country to use CGH to resolve the identity of aberrant chromosomal material.Methods: We report the use of CGH for the evaluation of 12 clinical postnatal cases in which traditional cytogenetic analysis yielded ambiguous results. This series consisted of five marker chromosomes, five unbalanced translocations, and two intrachromosomal duplications.Results: Identification and characterization of the additional unknown chromosomal material was achieved with use of CGH. All CGH findings were validated by traditional fluorescence in situ hybridization and other specialized staining techniques.Conclusions: These results demonstrate the effective use of CGH as a focused, single-step method for the identification of chromosomal material of unknown origin.

Loss of subtelomeric sequence associated with a terminal inversion duplication of the short arm of chromosome 4

We report on a 4(1/2)-year-old girl, who presented with multiple minor anomalies consistent with trisomy for 4p. GTG-banding identified a de novo terminal inversion duplication of distal 4p, dup(4)(p16.3p15.3). Fluorescence in situ hybridization (FISH) with a wcp4 probe confirmed the chromosome 4 origin of the additional material. FISH with a 4p subtelomere probe, D4F26, showed no signal on the dup(4) chromosome identifying a deletion of this region. Molecular analysis of 4p STS loci confirmed the subtelomeric deletion and showed loss of the paternal allele in this region. The paternal origin of the deleted region and homozygosity for one of the two paternal alleles within the region of the duplication suggests that a sister chromatid rearrangement on the paternal chromosome 4 was involved in the formation of the dup(4) chromosome. To date, the best characterized mechanisms of formation of chromosome duplications are terminal inversion duplications of 8p, which were shown to be derived from rearrangements at maternal meiosis-I. Our data show that mechanisms other than a maternal meiosis-I rearrangement can lead to the formation of terminal inversion duplications. FISH analysis with the appropriate subtelomeric probes is warranted in terminal inversion duplications to check for associated deletions.

Partial deletion of long arm of chromosome 11: del (11) (q23)

The cytogenetic analysis of an infant with multiple congenital anomalies revealed a small deletion of the long arm of one No. 11 chromosome: 46, XX, del(11)(q23). The main clinical manifestations included: ocular colobomata, absent philtrum, severe congenital heart disease, contractures of the large joints and skin pigmentation.

Skeletal defects in paternal uniparental disomy for chromosome 14 are re-capitulated in the mouse model (paternal uniparental disomy 12)

Human paternal uniparental disomy for chromosome 14 (upd(14)pat) presents with skeletal abnormalities, joint contractures, dysmorphic facial features and developmental delay/mental retardation. Distal human chromosome 14 (HSA14) is homologous to distal mouse chromosome 12 (MMU12) and both regions have been shown to contain imprinted genes. In humans, consistent radiographic findings include a narrow, bell-shaped thorax with caudal bowing of the anterior ribs, cranial bowing of the posterior ribs and flaring of the iliac wings without shortening or dysplasia of the long bones. Mice with upd(12)pat have thin ribs with delayed ossification of the sternum, skull and feet. In both mice and humans, the axial skeleton is predominantly affected. We hypothesize that there is an imprinted gene or genes on HSA14/MMU12 that specifically affects rib/thorax development and the maturation of ossification centers in the sternum, feet and skull with little effect on long bone development.

Trisomy 21 mosaicism in a woman with two children with trisomy 21 Down's syndrome

Trisomy 21 mosaicism was identified by fluorescent quinacrine banding in a phenotypically normal mother, who gave birth to two children with trisomy 21 Downs syndrome.

Alkaline phosphatase activity in cultured skin fibroblasts from fibrodysplasia ossificans progressiva.

Alkaline phosphatase activity in four strains of cultured skin fibroblasts obtained from a patient with fibrodysplasia ossificans progressiva was at the low normal range. The enzyme activity in normal fibroblasts significantly increased at late confluency. It appears that the high levels of alkaline phosphatase activity reported in biopsies of lesions are not genetically determined but are secondary events of local tissue reaction.

Prenatal diagnosis of 5p

With the combination of the various banding techniques (G, Q, and R), a small deletion of the short arm of a No. 5 chromosome was detected prenatally in the pregnancy of a 39–year‐old woman. The deletion appeared to be either interstitial in nature, involving part of p13 and p14, or the result of a translocation with deletion of pl3→pter. Both parents were found to have a normal chromosome constitution with normal banding patterns. Thus, this deletion was a de novo event. Repeat amniotic fluid cell chromosome analysis at the time of elective abortion, and postmortem examination of the fetus confirmed the prenatal cytogenetic diagnosis. We wish to emphasize that precise identification of a small deletion, as in this case, requires a combination of the various banding techniques.

Supernumerary small ring chromosome.

A supernumerary small ring chromosome was found in 30% of cultured peripheral leucocytes and 50% of skin fibroblasts in a 6-year-old boy with mild mental retardation and midline cleft palate. The extra chromosome appeared to carry a densely staining region on Giemsa banding. The banding patterns of the remaining 46 chromosomes were normal. C banding indicated that the ring chromosome contained mainly centromeric constitutive heterochromatin. Chromosome analysis of both parents showed normal karyotypes by both conventional and banding techniques; thus the origin of the ring chromosome could not be determined.

ASSOCIATION OF 5q- AND REFRACTORY ANEMIA

Specific chromosomal aberrations have begun to be recognized in hematologic disorders since the development of the current banding techniques. Within the last two years, six patients with refractory anemia have been reported from Belgium with a partial deletion of the long arm of one no. 5 chromosome (5q-). We have identified 5q- in another patient with refractory anemia. The patient is a 57 year old female with anemia for 3 years and headache for several months. Physical examination was within normal limits. There was no hepatosplenomegaly. The blood count revealed: Hb of 8.7; WBC 8200 with normal differential; platelets 689,000. There was poikilocytosis, anisocytosis and basophilic stippling. MCH, MCV, MCHC, Fe, Folate, B12, haptoglobin and LAP were normal. Alkaline resistant Hb was 4.8%. The bone marrow aspirate showed normocellularity with a slight increase in megakaryocytes and erythroblasts, and 8% myeloblasts. Direct bone marrow preparation without PHA stimulation showed a 5q- in 60% of the cells analyzed. Banding studies showed that the partial deletion involves the terminal 2/3 of the long arm of one no. 5. del(5)(q14). Therefore, it appears that 5q- is specifically associated with refractory anemia. It remains to be seen whether patients with refractory anemia and Sq- tend to develop acute leukemia subsequently as has been implied recently in 5 patients with acute myelogenous leukemia.