Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

Expansion of a 12-kb VNTR containing the REXO1L1 gene cluster underlies the microscopically visible euchromatic variant of 8q21.2

“…42 The 8q21.2 VNTR is one of the nine autosomal tandem arrays 42 kb that contain a single gene and show CNV. 27 Three of these nine have been associated with one or more traits including (1) higher copy number of the salivary amylase gene (AMY1) at 1q21.1 with high starch diets; 43 (2) increasing copy number of the 8p23.1 beta defensin genes with higher predisposition to psoriasis, 5,6 higher human immunodeficiency virus (HIV) load 7 and, possibly, resistance to influenza virus infection; 8 and (3) lower copy number of the CCL3L1 gene at 17q21.1 with weak protection against malarial anaemia 44 and susceptibility to chronic hepatitis C virus (HCV) infection. 45 It is therefore interesting that immunological reaction against the human REXO1L1 gene product (GOR) is a marker of HCV infection including occult HCV in which antibody assays against the HCV are negative.…”

“…These have been described as euchromatic variants (EVs) 2 (Chromosome Anomaly Collection) and involve (1) constitutional cytogenetic amplification of known CNV regions or (2) duplication, triplication or deletion of large segmentally duplicated (SD) euchromatic tracts which may include heterochromatin and accompany pseudo-dicentric variants (Table 1). Most of the EVs are clinically innocuous but the 8p23.1 EV has been associated with a number of traits [5][6][7][8] and the 4p16.1 EV co-segregated with microtia.…”

A new diagnostic workflow for patients with mental retardation and/or multiple congenital abnormalities: test arrays first

“…30,31 A large number of small rearrangements, detected in patients with MR and inherited from phenotypically normal parents, have been reported, whereby it was speculated that some of these imbalances may indeed be benign variations and others are likely to represent susceptibility loci for disease. 32,33 A particularly intriguing example is the submicroscopic 1q21 deletion, characteristic for thrombocytopenia absent radius syndrome, which is found in all patients with the syndrome, but is inherited from a phenotypically normal parent in a subset of cases. 34 It is becoming increasingly clear that many CNVs come with a highly variable phenotype, including what is considered as 'normal.'…”

“…35 Mechanisms that can explain why some inherited CNVs occasionally result in abnormal development have been postulated. 32,36 These mechanisms include: a mutation in the same region on the other chromosome; a mutation in one or more unlinked modifying genes; imprinting; mosaicism in one of the parents; or any other unidentified genetic, epigenetic or environmental factor. 21,32 Furthermore, it is frequently assumed that parents are phenotypically normal, although a closer inspection by a clinical geneticist might reveal subtle anomalies.…”

Recurrent copy number changes in mentally retarded children harbour genes involved in cellular localization and the glutamate receptor complex

“…Techniques allowing the detection of submicroscopic segmental aneuploidy have enabled us to pinpoint novel microdeletion and microduplication syndromes, such as CHARGE (coloboma, heart anomalies, chonal atresia, retardation, genital and ear anomalies), 5 Peters Plus, 6 recurrent 17q12 rearrangements, 7 del(17)(q21), 8,9 and the 22q13.3 deletion, 10 Pitt-Hopkins 11 and thrombocytopenia-absentradius syndromes 12 (for reviews see Lee and Lupski 3 and Slavotinek 13 ). In addition, clinically inconsequential segmental deletions [14][15][16] and segmental duplications in healthy individuals 17 have been reported. Studies involving array-based comparative genome hybridization (array-CGH), 18,19 representational oligonucleotide microarray analysis, 20 fosmid library insert mapping 21 and SNP inheritance analyses [22][23][24] indicate that copy number changes (CNCs) are frequently occurring polymorphisms in the genome of healthy individuals.…”