Metastatic medulloblastoma in an adolescent with Simpson-Golabi-Behmel syndrome.

We describe the case of a 12-year-old Hispanic male with a clinical and molecular diagnosis of Simpson-Golabi-Behmel Syndrome (SGBS) who subsequently developed metastatic medulloblastoma. While individuals with SGBS have been documented to have increased risk for intra-abdominal tumors such as Wilms tumor and neuroblastoma, medulloblastomas, or CNS tumors in general, have not been reported in patients with this syndrome. Our patient was clinically diagnosed with SGBS as an infant. He presented with many of the common features of the syndrome, such as cleft palate, macroglossia, post-axial polydactyly, "coarse" facial features, and ventricular septal defects (VSDs). Molecular testing performed in April 2009 confirmed the SGBS diagnosis. This testing detected a large intragenic deletion in the GPC3 gene (more than 500 kb, 8 exons) extending from intron 2, 37 kb downstream of exon 2, to the 5' end of the gene, deleting exons 1 and 2. However, subsequent testing by gene-centric high-density array comparative genomic hybridization (aCGH) detected a deletion encompassing only exon 2. Therefore, the exact 5' boundary of the deletion cannot currently be determined, due to an apparent complex rearrangement upstream of exon 1. We present this case of metastatic medulloblastoma as a unique malignancy in a patient with SGBS.

Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes.

Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed. Both of the breakpoint regions in 4p16.2 and 11p15.4 were narrowed to large ∼359-kb and ∼215-kb low-copy repeat (LCR) clusters, respectively, by aCGH and SNP array analyses. DNA sequencing enabled mapping the breakpoints of one translocation to 24 bp within interchromosomal paralogous LCRs of ∼130 kb in length and 94.7% DNA sequence identity located in olfactory receptor gene clusters, indicating nonallelic homologous recombination (NAHR) as the mechanism for translocation formation. To investigate the potential involvement of interchromosomal LCRs in recurrent chromosomal translocation formation, we performed computational genome-wide analyses and identified 1143 interchromosomal LCR substrate pairs, >5 kb in size and sharing >94% sequence identity that can potentially mediate chromosomal translocations. Additional evidence for interchromosomal NAHR mediated translocation formation was provided by sequencing the breakpoints of another recurrent translocation, der(8)t(8;12)(p23.1;p13.31). The NAHR sites were mapped within 55 bp in ∼7.8-kb paralogous subunits of 95.3% sequence identity located in the ∼579-kb (chr 8) and ∼287-kb (chr 12) LCR clusters. We demonstrate that NAHR mediates recurrent constitutional translocations t(4;11) and t(8;12) and potentially many other interchromosomal translocations throughout the human genome. Furthermore, we provide a computationally determined genome-wide "recurrent translocation map."

Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits and possibly Diamond--Blackfan anaemia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) can occur in isolation or in association with other abnormalities. We hypothesised that some cases of non-isolated CDH are caused by novel genomic disorders. METHODS AND RESULTS: In a cohort of >12, 000 patients referred for array comparative genomic hybridisation testing, we identified three individuals-two of whom had CDH--with deletions involving a ∼2.3 Mb region on chromosome 15q25.2. Two additional patients with deletions of this region have been reported, including a fetus with CDH. Clinical data from these patients suggest that recurrent deletions of 15q25.2 are associated with an increased risk of developing CDH, cognitive deficits, cryptorchidism, short stature and possibly Diamond-Blackfan anaemia (DBA). Although no known CDH-associated genes are located on 15q25.2, four genes in this region--CPEB1, AP3B2, HOMER2 and HDGFRP3--have been implicated in CNS development/function and may contribute to the cognitive deficits seen in deletion patients. Deletions of RPS17 may also predispose individuals with 15q25.2 deletions to DBA and associated anomalies. CONCLUSIONS: Individuals with recurrent deletions of 15q25.2 are at increased risk for CDH and other birth defects. A high index of suspicion should exist for the development of cognitive defects, anaemia and DBA-associated malignancies in these individuals.

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes.

PURPOSE: Genomic rearrangements of chromosome 22q11.2, including the microdeletion associated with DiGeorge/velocardiofacial syndrome, are mediated by nonallelic homologous recombination between region-specific low-copy repeats. To date, only a small number of patients with 22q11.2 microduplication have been identified. METHODS: We report the identification by array-comparative genomic hybridization of 14 individuals from eight families who harbor microduplications within the 22q11.2 region. RESULTS: We have now observed a variety of microduplications, including the typical common approximately 3-Mb microduplication, approximately 1.5-Mb nested duplication, and smaller microduplications within and distal to the DiGeorge/velocardiofacial syndrome region, consistent with nonallelic homologous recombination using distinct low-copy repeats in the 22q11.2 DiGeorge/velocardiofacial syndrome region. These microduplications likely represent the predicted reciprocal rearrangements to the microdeletions characterized in the 22q11.2 region. The phenotypes seen in these individuals are generally mild and highly variable; familial transmission is frequently observed. CONCLUSIONS: These findings highlight the unbiased ability of array-comparative genomic hybridization to identify genomic imbalances and further define the molecular etiology and clinical phenotypes seen in microduplication 22q11.2 syndrome. Our findings also further support that the 22q11.2 region is highly dynamic with frequent rearrangements using alternative low-copy repeats as recombination substrates.

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

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.