Chromosomal microarray analysis (CMA) detects a large X chromosome deletion including FMR1, FMR2, and IDS in a female patient with mental retardation

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 06/2007; 143A(12):1358-65. DOI: 10.1002/ajmg.a.31781
Source: PubMed


Chromosomal microarray analysis (CMA) by array-based comparative genomic hybridization (CGH) is a new clinical test for the detection of well-characterized genomic disorders caused by chromosomal deletions and duplications that result in gene copy number variation (CNV). This powerful assay detects an abnormality in approximately 7-9% of patients with various clinical phenotypes, including mental retardation. We report here on the results found in a 6-year-old girl with mildly dysmorphic facies, obesity, and marked developmental delay. CMA was requested and showed a heterozygous loss in copy number with clones derived from the genomic region cytogenetically defined as Xq27.3-Xq28. This loss was not cytogenetically visible but was seen on FISH analysis with clones from the region. Further studies confirmed a loss of one copy each of the FMR1, FMR2, and IDS genes (which are mutated in Fragile X syndrome, FRAXE syndrome, and Hunter syndrome, respectively). Skewed X-inactivation has been previously reported in girls with deletions in this region and can lead to a combined Fragile X/Hunter syndrome phenotype in affected females. X-inactivation and iduronate 2-sulfatase (IDS) enzyme activity were therefore examined. X-inactivation was found to be random in the child's peripheral leukocytes, and IDS enzyme activity was approximately half of the normal value. This case demonstrates the utility of CMA both for detecting a submicroscopic chromosomal deletion and for suggesting further testing that could possibly lead to therapeutic options for patients with developmental delay.

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    • "The entire genome is covered with an average resolution of 30 kb, excluding low-copy repeats and other repetitive sequences (https:// The procedures for DNA digestion, labeling, hybridization, and data analysis were performed as previously described [Probst et al., 2007]. "
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    ABSTRACT: Individuals with deletions of chromosome 5q12-13 have rarely been reported and have a range of phenotypes including postnatal growth restriction, intellectual disability, hyperactivity, and ocular abnormalities. Most individuals reported have large deletions or complex rearrangements which have made identifying genes responsible for these phenotypes challenging. Here we report an individual with a chromosome 5q12-13 deletion with intellectual disability, hyperactivity and restricted linear growth. Based on the location of our patient's deletion in relation to the previously reported deletions, we have narrowed the locus for postnatal growth restriction to less than 1 megabase. Further refinement of this locus with reports of additional individuals with deletions of this region will allow for better understanding of the gene(s) responsible for this phenotype. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Jul 2015 · American Journal of Medical Genetics Part A
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    • "However, the cause is still unknown in most patients with syndromic obesity. While copy number variations (CNVs) have been extensively evaluated among cohorts of children with ID associated with multiple congenital malformations and facial features, leading to around 12% of abnormalities [Miller et al., 2010], it has been studied only in a few patients with syndromic obesity [Lespinasse et al., 2004; Menten et al., 2005; Probst et al., 2007; Zung et al., 2007; Dasouki et al., 2011; D'Angelo et al., 2013]. Indeed, the overall diagnostic yield of microarraybased comparative genomic hybridization (array CGH) has not been established yet in such a cohort. "
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    ABSTRACT: Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6). © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Aug 2014 · American Journal of Medical Genetics Part A
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    • "We next considered other X-linked mental retardation conditions including Fragile X syndrome as the FMR1 gene is also located in the deletion region and FMR1 deletions are associated with Fragile X syndrome [7-10]. Following Clarke et al., 1992, at least three additional deletion Xq27 or Xq27-28 females with hemizygosity for FMR1 have been reported [12-15]. Similar to our patient, these females had non-specific characteristics of Fragile X syndrome such as hypotonia, speech, motor, and language delays, and cognitive impairment [19]. "
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    ABSTRACT: Background Global developmental delay and mental retardation are associated with X-linked disorders including Hunter syndrome (mucopolysaccharidosis type II) and Fragile X syndrome (FXS). Single nucleotide mutations in the iduronate 2-sulfatase (IDS) gene at Xq28 most commonly cause Hunter syndrome while a CGG expansion in the FMR1 gene at Xq27.3 is associated with Fragile X syndrome. Gene deletions of the Xq27-28 region are less frequently found in either condition with rare reports in females. Additionally, an association between Xq27-28 deletions and skewed X-inactivation of the normal X chromosome observed in previous studies suggested a primary role of the Xq27-28 region in X-inactivation. Case presentation We describe the clinical, molecular and biochemical evaluations of a four year-old female patient with global developmental delay and a hemizygous deletion of Xq27.3q28 (144,270,614-154,845,961 bp), a 10.6 Mb region that contains >100 genes including IDS and FMR1. A literature review revealed rare cases with similar deletions that included IDS and FMR1 in females with developmental delay, variable features of Hunter syndrome, and skewed X-inactivation of the normal X chromosome. In contrast, our patient exhibited skewed X-inactivation of the deleted X chromosome and tested negative for Hunter syndrome. Conclusions This is a report of a female with a 10.6 Mb Xq27-28 deletion with skewed inactivation of the deleted X chromosome. Contrary to previous reports, our observations do not support a primary role of the Xq27-28 region in X-inactivation. A review of the genes in the deletion region revealed several potential genes that may contribute to the patient’s developmental delays, and sequencing of the active X chromosome may provide insight into the etiology of this clinical presentation.
    Full-text · Article · May 2013 · BMC Medical Genetics
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