Submicroscopic Chromosomal Deletions Research Articles

A novel 5q11.2 deletion detected by microarray comparative genomic hybridisation in a child referred as a case of suspected 22q11 deletion syndrome

The 22q11 deletion syndrome (22q11DS) is a developmental syndrome comprising of heart, palate, thymus and parathyroid glands defects. Individuals with 22q11DS usually carry a 1.5- to 3-Mb heterozygous deletion on chromosome 22q11.2. However, there are many patients with features of 22q11DS without a known cause from conventional karyotype and FISH analysis. Six patients with features of 22q11DS, a normal chromosomal and FISH 22q11 analysis, were selected for investigation by microarray genomic comparative hybridisation (array CGH). Array-CGH is a powerful technology enabling detection of submicroscopic chromosome duplications and deletions by comparing a differentially labelled test sample to a control. The samples are co-hybridised to a microarray containing genomic clones and the resulting ratio of fluorescence intensities on each array element is proportional to the DNA copy number difference. No chromosomal changes were detected by hybridisation to a high resolution array representing chromosome 22q. However, one patient was found to have a 6-Mb deletion on 5q11.2 detected by a whole genome 1-Mb array. This deletion was confirmed with fluorescence in-situ hybridisation (FISH) and microsatellite marker analysis. It is the first deletion described in this region. The patient had tetralogy of Fallot, a bifid uvula and velopharyngeal insufficiency, short stature, learning and behavioural difficulties. This case shows the increased sensitivity of array CGH over detailed karyotype analysis for detection of chromosomal changes. It is anticipated that array CGH will improve the clinician's capacity to diagnose congenital syndromes with an unknown aetiology.

Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features

The underlying causes of learning disability and dysmorphic features in many patients remain unidentified despite extensive investigation. Routine karyotype analysis is not sensitive enough to detect subtle chromosome rearrangements (less...

Linkage of preaxial polydactyly type 2 to 7q36

We have characterized a 6-generation North American Caucasian kindred segregating one form of preaxial polydactyly type 2 (PPD-2). We demonstrate linkage to the 7q36 region and describe a submicroscopic telomeric chromosomal deletion in phase with the PPD-2 phenotype. Recently, several kindreds segregating triphalangeal thumb (TPT) with and without associated hand anomalies (syndactyly and/or postaxial polydactyly) have also been linked to the subtelomeric region of chromosome 7q [Heutink et al., 1994: Nat Genet 6:287-291; Tsukurov et al., 1994: Nat Genet 6:282-286]. We demonstrate by haplotype analysis that our North American pedigree represents a PPD allele that is independent of the founder PPD allele present in the previously described kindreds.

Psychiatric genetics: research challenges and pathways forward.

Lessons from past psychiatric genetic research, together with key issues in psychiatry requiring genetic investigation, are reviewed in order to consider the implications for the ways forward. It is argued that traditional quantitative genetics needs to use a combination of twin, adoptee, and family strategies, to examine continuities and discontinuities in psychopathology between childhood and adult life, to compare dimensions and categories, to employ adequate conceptualization and measurement of disorders, to use statistical techniques based on latent constructs, to use biological trait indicators where possible, to examine risk factors as well as diseases, to include good measures of postulated environmental risk variables, to study the interplay between genes and environment, and to study the key assumptions underlying genetic strategies. Molecular cytogenetics needs to consider both the general and specific psychopathological risks associated with chromosome abnormalities and to examine the mechanism involved, to examine the role of submicroscopic chromosomal deletions and of mitochondrial disorders, and to investigate the mechanisms involved in trinucleotide repeat amplifications that take place during intergenerational transmission. Molecular genetics needs to make greater use of smaller pedigrees in view of the concerns over phenotypic definition and genetic heterogeneity in very large extended dense pedigrees, to use sib-pair designs in view of the likelihood that most psychiatric disorder will prove to be multifactorial, to combine association strategies with linkage analyses, to pay careful attention to the definition of phenotypes in probands, to remain in close touch with other branches of biological psychiatry, and to make effective use of collaboration between centers. To date, transgenic models have had a rather limited application in psychiatry but, despite their difficulties, they are likely to provide an underpinning for gene therapy in disorders where that seems feasible.

The Norrie disease gene maps to a 150 kb region on chromosome Xp11.3.

Norrie disease is a human X-linked recessive disorder of unknown etiology characterized by congenital blindness, sensory neural deafness and mental retardation. This disease gene was previously linked to the DXS7 (L1.28) locus and the MAO genes in band Xp11.3. We report here fine physical mapping of the obligate region containing the Norrie disease gene (NDP) defined by a recombination and by the smallest submicroscopic chromosomal deletion associated with Norrie disease identified to date. Analysis, using in addition two overlapping YAC clones from this region, allowed orientation of the MAOA and MAOB genes in a 5'-3'-3'-5' configuration. A recombination event between a (GT)n polymorphism in intron 2 of the MAOB gene and the NDP locus, in a family previously reported to have a recombination between DXS7 and NDP, delineates a flanking marker telomeric to this disease gene. An anonymous DNA probe, dc12, present in one of the YACs and in a patient with a submicroscopic deletion which includes MAOA and MAOB but not L1.28, serves as a flanking marker centromeric to the disease gene. An Alu-PCR fragment from the right arm of the MAO YAC (YMAO.AluR) is not deleted in this patient and also delineates the centromeric extent of the obligate disease region. The apparent order of these loci is telomere ... DXS7-MAOA-MAOB-NDP-dc12-YMAO.AluR ... centromere. Together these data define the obligate region containing the NDP gene to a chromosomal segment less than 150 kb.

Assignment of the gene for neuroendocrine protein 7B2 ( SGNE1 locus) to mouse chromosome region 2[E3–F3] and to human chromosome region 15q11-q15

The gene for 7B2, a protein found in the secretory granules of neural and endocrine cells (gene symbol SGNE1) was localized to the E3–F3 region of mouse chromosome 2 and to the q11–q15 region of human chromosome 15. This was determined by in situ hybridization, using a mouse 7B2 cDNA and an intronic fragment of the corresponding human gene as probes. The respective locations of SGNE1 in the two species correlate with the conservation of loci between these subregions of mouse chromosome 2 and human chromosome 15. Clinically, the human SGNE1 DNA fragment may serve as a molecular probe of this locus in both the Prader-Willi and the Angelman syndromes, which are often accompanied by submicroscopic chromosomal deletions in the 15q11–15q13 region.

Biochemistry and genetics of monoamine oxidase

This chapter reviews the two mitochondrial flavin containing isozymes of monoamine oxidase. Section 1, “Biochemistry” discusses assays, substrates and inhibitors, phylogenic and tissue distribution, interactions with lipids, nutritional studies, protein structure, kinetic and chemical mechanistic proposals, and biosynthesis. Section 2, “Inheritance” discusses possible genes involved in expression, genetic studies of platelet MAO-B and fibroblast MAO-A, and chromosomal location. Section 3, “Molecular Genetics” reviews the cloning of their cDNAs, their intra- and interspecies homology and structural inferences made from deduced amino acid sequences. Section 4, “Regulation” gives an overview of levels in development and aging, and effect of drugs. The final section 5, “Role in Human Disease” dicusses physiological function and effects of altered levels in humans and animal models including complete absence due to a submicroscopic chromosomal deletion in several human patients.

Gene diagnosis in X-linked ichthyosis

Three families segregating for X-linked ichthyosis (XLI) were analysed using the full-length STS cDNA probe and an anonymous polymorphic DNA sequence closely linked to the STS gene. In patients from two of the families, submicroscopic chromosomal deletions could be detected using both the STS and the GMGX9 (DXS237 locus) probes. Patients in the third family showed the same hybridization pattern as healthy males following molecular hybridization with either of the probes. The results of DNA analysis (indirect genotype diagnosis) agree well with those based on the arysulfatase C/beta-gal determination and prove the reliability of the biochemical test. Both methods are discussed for carrier detection, prenatal diagnosis, and genetic counseling.