Herman E. Wyandt

Schizophrenia susceptibility gene locus at Xp22.3

Multiple genetic loci have been implicated in the search for schizophrenia susceptibility genes, none having been proven as causal. Genetic heterogeneity is probable in the polygenic etiology of schizophrenia. We report on two unrelated Caucasian women with paranoid schizophrenia (meeting Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria) who have an Xp22.3 overlapping deletion characterized by fluorescence in situ hybridization (FISH). Patient 1 was previously reported by us (Wyandt HE, Bugeau‐Michaud L, Skare JC, Milunsky A. Partial duplication of Xp: a case report and review of previously reported cases. Amer J Med Genet 1991: 40: 280–283) to have a de novo partial duplication of Xp. At that time, she was a 24‐year‐old woman with short stature, irregular menses, other abnormalities suggestive of Turner syndrome, and paranoid schizophrenia. Recently, FISH analysis demonstrated that she has an inverted duplication (X)(p22.1p11.2) and a microscopic deletion (X)(p22.2p22.3) between DXS1233 and DXS7108 spanning approximately 16–18 cM. Patient 2 is a 14‐year‐old girl with short stature, learning disabilities, and paranoid schizophrenia. High‐resolution chromosome analysis revealed a de novo deletion involving Xp22. FISH analysis showed that the deletion (X)(p22.2p22.3) spanned 10–12 cM between AFMB290XG5 and DXS1060. Given that deletions of Xp22 are not common events, the occurrence of two unrelated schizophrenia patients with an overlapping deletion of this region would be extraordinarily rare. Hence, the deletion within Xp22.3 almost certainly contains a gene involved in the pathogenesis of paranoid schizophrenia.

Molecular cytogenetic characterisation of the first familial case of partial 9p duplication (p22p24).

We report on a father and daughter with a partial 9p duplication, dup(9)(p22p24). Their phenotype, albeit mild, is characteristic of partial trisomy 9p. Fluorescence in situ hybridisation (FISH) was used to characterise further and confirm the G banding finding. This is the first reported instance of trisomy 9p occurring in two successive generations. The duplicated segment in these two patients is among the smallest segments reported. Comparison of our two patients and 144 reported patients with trisomy 9p (partial or complete trisomy) suggests that the 9p22 region may be responsible for the observed phenotype in 9p duplication cases.

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.

Cytogenetic studies of eight squamous cell carcinomas of the head and neck : deletion of 7q, a possible primary chromosomal event

Cytogenetic analysis was performed on the metaphase spreads obtained from primary cultures of eight squamous cell carcinomas (SCCa) of the head and neck. Despite a variety of tumor sites and clinical stages, four of eight tumors studied showed the same interstitial deletion of a portion of the q arm of chromosome 7, i.e., del(7)(q22q34). In one tumor, this was the sole chromosome abnormality present. Three tumors showed multiple chromosome rearrangements, including deletion at 7q. Three tumors showed multiple rearrangements but did not have del(7q). One tumor had an apparently, normal karyotype. The implications for del(7q) as a primary chromosomal event in SCCa are discussed.

Partial Xq25 deletion in a family with the X-linked lymphoproliferative disease (XLP)

X-linked lymphoproliferative disease (XLP) results in exquisite vulnerability to EBV infection: fatal infectious mononucleosis (IM), acquired hypogammaglobulinemia and/or malignant lymphoma occur invariably following infection with the virus. We have identified the XLP locus using the DXS42 DNA probe having restriction length polymorphisms (RFLP). We report an interstitial deletion involving a portion of the Xq25 region in the X chromosome of an affected male, one sister, and their mother. Concordance has been established between the presence of a deletion and RFLP linkage analysis with the DXS42 probe in the kindred. This finding will contribute substantially to the mapping, cloning, and sequencing of the gene responsible for XLP.

Report of a variant t(1;15;17)(p36;q22;q21.1) in a patient with acute promyelocytic leukemia

Chromosome analysis of bone marrow aspirate from a 46-year-old man with acute promyelocytic leukemia (APL) revealed a variant translocation, 46,XY,t(1:15;17)(p36;q22;q21.1). The breakpoints in chromosomes 15 and 17 appear to be the same as those in the more common translocation, t(15;17), associated with APL. The common translocation has been reported in up to 80% of cases of APL. Seventeen cases with variant translocations have been reported involving 15 alone, 17 alone, or 15, 17, and some other chromosome.

Fluorescence in situ hybridization to assess aneuploidy for chromosomes 7 and 8 in hematologic disorders

Stored, fixed cell suspensions of bone marrows from 70 patients karyotyped over a three-year period for myelodysplastic syndrome (MDS) or related hematologic conditions were retrospectively studied in two series using centromeric probes for chromosomes 7 and 8. Series I consisted of patient samples with numerical and/or structural abnormalities of chromosomes 7 or 8, matched with chromosomally normal samples from about the same time period. Series II consisted of consecutive MDS patient samples as well as patient samples in which one or more cells had numerical or structural abnormalities of 7 and 8. In both series, probes for chromosomes 7 and 8 were applied in each case and at least 100 nuclei were scored for each probe for the distribution of one, two, or three signals. Twenty-seven cases had clonal abnormalities by routine cytogenetics (RC): 12 with monosomy 7; one with monosomy 8; five with trisomy 8; nine with clonal abnormalities other than 7 or 8 aneuploidy. Eleven cytogenetically normal cases gave abnormal interphase FISH (IF) results; one was subsequently confirmed by metaphase FISH analysis to have a clonal structural abnormality of chromosome 7; one case with a trisomy 8 clone, in remission by RC, showed 35% of cells by IF with three signals for chromosome 8; one case had heteromorphic chromosomes by FISH. Of eight remaining cases, five (four with -7 and one with +8 by IF) were among 22 cases of cytogenetically normal MDS. Three remaining cases (two with +8 and one with both +7 and +8 by IF) had AML or MPD. The high rate of possible undetected monosomy 7, among MDS cases in particular, suggests all MDS cases should be screened by IF.

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.

Molecular cytogenetic characterization of multiple intrachromosomal rearrangements of chromosome 2q in a patient with Waardenburg's syndrome and other congenital defects

At 6 years of age, a boy with bilateral sensorineural deafness, lateral displacement of inner canthi, a bulbous nasal tip, synophrys, and cryptorchidism was clinically diagnosed as having Waardenburgs syndrome type I (WS‐1). In addition, he had a lumbar spina bifida with hydrocephalus shunted on the second day of life and severe mental retardation with a head circumference at the fifth percentile. Neither parent showed signs of WS‐1, and the family history was negative. Because of the WS‐1 features, attention was focused on the PAX3 location in 2q, at which time a de novo paracentric inversion of 2q23–q37.1 was noted. Subsequent high‐resolution chromosome analysis 8 years later indicated a complex rearrangement involving regions 2q31–q35 and 2q13–q21. Whole chromosome painting and high‐resolution comparative genomic hybridization yielded negative results for any translocation, duplication, or deletion of any chromosome segments. Sequencing of the PAX3 gene yielded no detectable mutation. Fluorescent in situ hybridization (FISH) studies with human BAC clones revealed five breakpoints in chromosome 2q resulting in two paracentric inversions and one insertion, the karyotype being interpreted as 46,XY,der(2)inv(2)(q13q21)inv(2)(q21q24.2)ins(2)(q24.2q33q35). In this extremely rare chromosomal rearrangement, the FISH result showed a breakpoint at 2q35 being proximal to and without involvement of the PAX3 gene. While further studies continue, possible interpretations include involvement of a regulatory gene(s) for PAX 3 and other genes at the other breakpoints related causally to the spina bifida and mental retardation.

Localization of the gene for human heart fatty acid binding protein to chromosome 1p32-1p33

Heart fatty acid binding protein (hFABP) is an abundant 14-kDa cytosolic protein thought to be involved in trafficking of fatty acids from the plasma membrane to sites of β-oxidation in mitochondria and peroxisomes and to the endoplasmic reticulum for lipid synthesis. A human hFABP cDNA isolated by polymerase chain reaction was used as a probe for in situ hybridization to metaphase chromosomes. A fragment of the gene for human hFABP was used as a probe for fluorescence in situ hybridization to metaphase chromosomes. The cDNA and genomic probes both localized the gene for human hFABP to chromosome 1p32-1p33.