Vijay Tonk

Atlas of human chromosome heteromorphisms

1. Introduction.- 2. Methods of Studying Human Chromosomes and Nomenclature.- 3. Normal Population Studies.- 4. Heteromorphisms in Clinical Populations.- 5. Technical Variables and the Use of Heteromorphisms in the Study of Human Chromosomes. A: Paternity Testing. B: Origin of Chromosome Abnormalities.- 6. Euchromatic Variants.- 7. FISH Technologies.- 8. Molecular Dissection of Heteromorphic Regions.- 9. Evolution of Human Alpha Satellite Sequences Comprising Variant Centromeric Chromosome Regions.- II: Plates.

Correlation of abnormal rapid FISH and chromosome results from amniocytes for prenatal diagnosis.

Rapid fluorescence in situ hybridization (FISH) performed on 1,788 amniocenteses, using Aneuvision (Vysis) probes for chromosomes 13, 18, 21, X, and Y, over several years, yielded 115 cases with percentages of aneuploidy between 4 and 100%. All cases above 60% were confirmed to be positive by chromosome analysis. Fifteen of forty-one cases that would be considered inconclusive by generally accepted criteria (i.e. with less than 60% of cells with an abnormal signal pattern) revealed lower cutoffs to be positive when confirmed by chromosome analysis. For trisomy 21, 6 cases with percentages from 36 to 57% were positive; 4 of 7 cases with percentages from 22.5 to 33% were positive; 11 cases with percentages of 13% or less were negative. Similar trends were found for aneuploidies of 13, 18, X, and Y. However, the number of abnormal cases is still too small to determine definitive cutoffs in the <60% gray zone. An average of 57 metaphases was analyzed for cases with FISH percentages below 60%. Despite the wide range of abnormal FISH percentages for chromosomally positive cases, we found no examples of autosomal mosaicism in this series. Although sex chromosome mosaicism was cytogenetically evident in several cases, there was little direct correlation between cytogenetic and rapid FISH results. FISH results involving sex chromosomes were more frequently confounded by maternal cell contamination and other technical factors.

Cytogenetic and molecular cytogenetic studies of a case of interstitial deletion of proximal 15q

A 4‐month‐old child with multiple anomalies was determined to have an interstitial deletion of chromosome 15, i.e., del(15) (q12q14). The deletion appears not to be a typical deletion of 15q12 such as seen in Angelman and Prader‐Willi syndromes, but appears to be more distal, involving either loss of all of 15q12 and part of 15q14, or part of 15q12 and most of 15q14. In either case, 15q13 is missing. Fluorescent in situ hybridization with probes for 15 centromere (D15Z), pericentromeric satellite sequences (D15Z1), and chromosome 15 painting probes shows the deleted chromosome to involve only 15 and no other acrocentric chromosome. Hybridization with probes for the AS and PWS loci (D15S11 and GABAB3, Oncor) show both sites to be intact in the deleted 15. The case is compared with two other reports with overlapping interstitial deletions of proximal 15q, neither of which shows typical features of Angelman or Prader‐Willi syndromes.

Duplication of 1q in a Child with Down Syndrome and Myelodysplastic Syndrome

Cytogenetic analysis of bone marrow cells was performed on a 2-year-old African-American male with Down syndrome (DS) and myelodysplastic syndrome (MDS), specifically refractory anemia with excess blasts in transformation (RAEB-T). Chromosome analysis showed, in addition to the constitutional trisomy 21, a trisomy of chromosome 11 and a dup(1)(q23q31). This duplication of 1q is apparently a new chromosomal abnormality in a child with MDS. Partial trisomy of the long arm of chromosome 1 has been reported by several authors and appears to represent a nonrandom chromosomal anomaly in patients with MDS/acute myelogenous leukemia and DS.

Normal Population Studies

The first major population studies of human chromosomes were an eventual collaborative effort with data collected from 56 952 newborns from six different countries [1–7]. These, for the larger part, were initiated on unbanded chromosome material and in most centers were based on examination of two to five metaphases from each subject. The frequency of major chromosome abnormalities from these studies forms the basis of much of the statistical knowledge relating to frequencies of the major chromosome abnormalities, both numerical and structural. In tabulations of the results of these studies [8], however, there was a conscious effort to exclude normal morphological variants. The rationale for this was that, even though variants of certain chromosomes were well known, chromosome banding techniques were discovered before most of these studies were completed, so that it was quickly realized that accurate determination of variants in the majority of chromosomes was not possible in non-banded material. Nevertheless, a specific attempt to assess variants in unbanded chromosomes from 4482 consecutive newborns was made by Lubs and Ruddle [9] in New Haven, Connecticut. Their study included 3476 infants of White mothers and 807 infants of Black mothers. All of the children were phenotypically normal except for one White child with low birth weight. Criteria for the most common variants were established for chromosomes A1, C9, E16, the short arms and satellites of D and G group chromosomes, and Y long arm. A total of 2131 variants were scored.

Autism: A Different Vision

Genomic analysis has emphasized the enormous genetic contribution to autism spectrum disorders, with over 80% of patients having changes demonstrable by high resolution chromosome (microarray) analysis or whole exome sequencing. An overview of these genetic changes demonstrates the expected role of synaptic transmission in autism and, together with clinical observations, emphasizes the importance of visual input on developing sensory systems and social responses. Neonatal recognition of autism predisposition through genetic analysis could allow sensory stimulation therapies during periods of neuroplasticity, an approach analogous to strabismus correction before the cortical dissociation of the deviant eye.

Deletion of 15q12 in Angelman syndrome: report of 3 new cases

Deletion of 15q12 has been reported in patients with Angelman syndrome (AS). We report chromosome studies showing del(15q12) in three new cases, diagnosed as having AS. We were also able to determine, through heteromorphism studies, that the origin of the deleted chromosome in all three probands is maternal. This is a consistent finding in previously reported cases of AS.