The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome

Abstract

Purpose: The advent of molecular cytogenetic technologies has altered the means by which new microdeletion syndromes are identified. Whereas the cytogenetic basis of microdeletion syndromes has traditionally depended on the serendipitous ascertainment of a patient with established clinical features and a chromosomal rearrangement visible by G-banding, comparative genomic hybridization using microarrays has enabled the identification of novel, recurrent imbalances in patients with mental retardation and apparently nonspecific features. Compared with the "phenotype-first" approach of traditional cytogenetics, array-based comparative genomic hybridization has enabled the detection of novel genomic disorders using a "genotype-first" approach. We report as an illustrative example the characterization of a novel microdeletion syndrome of 1q41q42. Methods: We tested more than 10,000 patients with developmental disabilities by array-based comparative genomic hybridization using our targeted microarray. High-resolution microarray analysis was performed using oligonucleotide microarrays for patients in whom deletions of 1q41q42 were identified. Fluorescence in situ hybridization was performed to confirm all 1q deletions in the patients and to exclude deletions or other chromosomal rearrangements in the parents. Results: Seven cases were found with de novo deletions of 1q41q42. The smallest region of overlap is 1.17 Mb and encompasses five genes, including DISP1, a gene involved in the sonic hedgehog signaling pathway, the deletion of which has been implicated in holoprosencephaly in mice. Although none of these patients showed frank holoprosencephaly, many had other midline defects (cleft palate, diaphragmatic hernia), seizures, and mental In 1963, Black and Carter 1 posited that the "elfin"-like facies characteristic of two clinical entities, supravalvular aortic stenosis and infantile hypercalcemia, suggested that the two disorders may be related. Nine years later, Beuren 2 demonstrated that supravalvular aortic stenosis and idiopathic infantile hypercalcemia, were, in fact, components of the same disorder,

Chromosomal microarray analysis as a first-line test in pregnancies with a priori low risk for the detection of submicroscopic chromosomal abnormalities

“…[27][28][29][30] The combined data from published prospective studies represent now a cohort of over 13 000 prenatal samples [7][8][9][10][11][12][13][14][15][16][17][18][19][22][23][24][26][27][28][29][30] (Table 1). Taken together, their findings clearly indicate that the use of CMA in prenatal diagnosis produces a substantial improvement in the detection rate of pathogenic chromosome abnormalities compared with conventional karyotyping.…”

“…CMA allows detection of microscopic and submicroscopic copy number variants (CNVs), as small as 50-100 Kb, B100 times smaller than the changes that can be identified by traditional karyotyping. [7][8][9][10] CMA is now recognized as the appropriate first-line test, in place of conventional karyotyping, for the clinical evaluation of postnatal patients with developmental delay/intellectual disability, multiple congenital anomalies and/or autism spectrum disorders. 3,4,6,8,[11][12][13][14] This change from conventional karyotyping to CMA in postnatal cytogenetics has generated an increasing interest in determining whether CMA will offer any advantages for the detection of fetal chromosomal abnormalities in prenatal diagnostics.…”

A functional analysis of GABARAP on 17p13.1 by knockdown zebrafish

“…1 Recently, the use of whole-genome scanning with array-based comparative genome hybridization (aCGH) has enabled the more accurate delineation of subtle chromosomal rearrangements. [2][3][4][5] Many novel microdeletion and duplication syndromes have been characterized using this revolutionary cytogenetic testing; 6,7 for example, 1q41q42 deletion syndrome, 8 15q13.3 deletion syndrome, 9 16p11.2 deletion syndrome, 10,11 17q12 deletion syndrome 12 and 17q21.31 deletion/duplication syndrome. [13][14][15] Despite its small size as compared with other chromosomes, chromosome 17 is associated with many newly characterized genomic syndromes.…”

Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome

“…[1][2][3] These methods have proven invaluable in the elucidation of genomic regions associated with mental retardation and/or congenital anomalies. [4][5][6][7][8] Several clinically distinct microdeletion and microduplication syndromes have been reported on the basis of data derived from these techniques, such as the 17q21.31 microdeletion syndrome 5 and the 1q41-1q42 microdeletion syndrome, 9 as well as microduplication syndromes involving 7q11.23 10,11 and 17p11.2. 12 The phenotypic characteristics of microdeletion syndromes can be caused by haploinsufficiency of single genes, for example, TCF4 (MIM 602272) in Pitt-Hopkins syndrome, 13 EHMT1 (MIM 607001) in the 9q34.3 subtelomeric deletion syndrome 14 and either CREBBP (MIM 600140) or EP300 (MIM 602700) in Rubinstein-Taybi syndrome.…”