ISOCHROMOSOME NEOCENTROMERE 15qter MOSAICISM Siri Huston, Yvette Rush, Tom Hempel, Ann Olney, Hope Chipman and Warren G. Sanger University of Nebraska Medical Center, Omaha, NE

ABSTRACT A 36 year-old female was seen in our genetics clinic for evaluation of mild mental retardation and possible Fragile X Syndrome. She had findings suggestive of a syndrome causing mild to borderline mental retardation, overgrowth, and dysmorphic features. Fragile X testing results were normal, however, chromosome studies showed mosaicism for a marker chromosome. A small supernumerary marker chromosome in 30% of the G-banded metaphases from peripheral blood was present. All human centromere FISH studies were negative for the marker. Subsequent molecular cytogenetic (FISH) studies characterized this marker to be of chromosome 15 origin. This marker was positive for two copies of the chromosome 15q subtelomere region but was negative for a centromere. Specifically, these results are positive for an iso neocentromere 15qter. The nomenclature was interpreted as mos 47,XX,+mar[6]/46,XX[14]/.ish i neo(15)(q26.3). This patient is therefore a mosaic for tetrasomy for the terminal region of the long arm of chromosome 15.

INTRODUCTION Small supernumerary chromosomes are also known as marker chromosomes, without further molecular characterization. The symptoms associated with such a chromosomal finding depend on the genetic origin of the extra structurally abnormal chromosome. Many marker chromosomes remain unidentified by routine cytogenetic studies. During recent years, progress has been made by the introduction of molecular cytogenetic studies (FISH) as a method to identify marker chromosomes. In many published cases, the centromeric origin has been established by using centromere-specific probes. Unfortunately, some marker chromosomes fail to show labeling with these probes. We present a case that recent chromosome studies in our lab showed the presence of mosaicism for a marker chromosome in 30% of the cells analyzed from a peripheral blood study (Figure 1). With the use of FISH, it was found that this marker chromosome was positive for two copies of the 15q subtelomere region, but negative for the SNRPN region and a centromere (Figure 2). The lack of a centromere signal was confirmed by hybridization with an all-human alpha-satellite probe (Figure 3). Thus, we were able to identify this marker as an isochromosome of the 15q terminus with a neocentromere. This patient is therefore a mosaic for tetrasomy of 15qter.

Figure 2 Figure 3

Figure 1 DISCUSSION Our patient is a 36 year-old female with a history of learning disabilities, mild developmental delay, dysmorphic features and overgrowth. She completed high school, with significant assistance through special education. She continues to live with her parents, and has had occasional employment outside the home. She was referred to our genetics clinic for evaluation of mild mental retardation and possible Fragile X Syndrome. Fragile X testing was normal, however, the chromosome studies showed the presence of mosaicism for a marker chromosome. We observed a small supernumerary marker chromosome in 30% (6 out of 20) of the G-banded metaphase cells from peripheral blood. Subsequent FISH studies examined the marker chromosome and confirmed that the marker chromosome was an isochromosome of the 15q terminal region with a neocentromere. This marker was positive for two copies of the chromosome 15q subtelomere region but was negative for a centromere. Specifically, these results are positive for an isochromosome neocentromere 15qter. This patient is therefore a mosaic for tetrasomy for the terminal region of the long arm of chromosome 15. It is likely that this marker chromosome was present at conception, with subsequent spontaneous loss of the marker chromosome in some cells, resulting in mosaicism. The biological parents of this patient subsequently had chromosome analysis. Neither parent has the marker chromosome; thus, this appears to be a new chromosome aberration in this family. The family history is negative for other individuals with similar developmental delays or overgrowth features.

RESULTS AND CONCLUSIONS The significance of a marker chromosome is variable. This is related to the specific origin of material involved in the marker. In our case, we know that there are two copies of part of the long arm of chromosome 15, which does not include SNRPN or a centromere. There are very few documented cases or any well-known conditions that involve tetrasomy 15qter; however, a few individuals with similar test results have been reported in the literature. Increased postnatal growth, mental retardation and learning disabilities are similar characteristics reported to be associated with this chromosomal abnormality. However, both of those patients in the literature were described to have specific physical differences including low-set ears, a big nose, small recessed chin, and an asymetric head and chest, but the piece of chromosome 15 involved in these patients was a much larger piece of material than was observed in our particular patient. Some of the same characteristics that our patient has fit with those described in the literature, so it appears that most likely this chromosomal abnormality is directly the cause of these similarly described features. Chromosome studies on both parents of our patient were normal, so we would expect the siblings to also have normal chromosomes. However, our clinical staff counseled the patient that if she decides to become pregnant, an amniocentesis would be available to test the fetus, as there is a risk to pass on the extra marker chromosome. The patient was advised that precise risks are difficult to determine as marker chromosomes may be unstable during meiosis.