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.
"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. "
"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 . "
[Show abstract][Hide abstract] 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.
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.
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.
BMC Medical Genetics 05/2013; 14(1):49. DOI:10.1186/1471-2350-14-49 · 2.08 Impact Factor
"The entire genome is covered with an average resolution of 30 kb, excluding low-copy repeats and other repetitive sequences (https://www.bcm.edu/geneticlabs). The procedures for DNA digestion, labeling, hybridization, and data analysis were performed as previously described [Probst et al., 2007]. FISH was performed with test probe for 14q32.33 "
[Show abstract][Hide abstract] ABSTRACT: Chromosome 14q32.3 deletions are uncommon, with most described patients harboring a ring chromosome 14. Only 15 deletions have been described not associated with ring formation or other complex chromosomal rearrangements. Here, we describe a child with the smallest deletion of chromosome 14q32.3 reported in the literature. This child's deletion encompasses at most 0.305 Mb and six genes including NUDT14, BRF1, BTBD6, PACS2, MTA1, and TEX22. He has similar clinical findings, including mild facial dysmorphisms and intellectual disability, as other individuals with much larger deletions of the terminus of the long arm of chromosome 14. This suggests that the genes deleted in our patient contribute to the 14q32 deletion syndrome.
American Journal of Medical Genetics Part A 08/2012; 158A(8):1962-6. DOI:10.1002/ajmg.a.35289 · 2.16 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.