Advances in overgrowth syndromes: clinical classification to molecular delineation in Sotos syndrome and Beckwith-Wiedemann syndrome

Cytrynbaum, Cheryl; Smith, Adam C.; Rubin, Tamar; Weksberg, Rosanna

doi:10.1097/01.mop.0000187191.74295.97

Cited by 20 publications

(11 citation statements)

References 49 publications

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“…Although only a few liveborn children with UPD 16 have been recognized, the reported experience does not suggest that UPD 16 can cause the abnormalities observed in Patient 1658 [60,61]. Paternal UPD 11p15 can produce Beckwith-Wiedemann syndrome [62], but this phenotype is very different from that observed in the affected child in Family 6904. However, as both of these cases involved isodisomy of a portion of the chromosome, we cannot rule out the possibility that the abnormal phenotype was produced by homozygosity for a recessive mutant allele [63,64].…”

Section: Discussionmentioning

confidence: 99%

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

et al. 2009

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BackgroundArray genomic hybridization is being used clinically to detect pathogenic copy number variants in children with intellectual disability and other birth defects. However, there is no agreement regarding the kind of array, the distribution of probes across the genome, or the resolution that is most appropriate for clinical use.ResultsWe performed 500 K Affymetrix GeneChip® array genomic hybridization in 100 idiopathic intellectual disability trios, each comprised of a child with intellectual disability of unknown cause and both unaffected parents. We found pathogenic genomic imbalance in 16 of these 100 individuals with idiopathic intellectual disability. In comparison, we had found pathogenic genomic imbalance in 11 of 100 children with idiopathic intellectual disability in a previous cohort who had been studied by 100 K GeneChip® array genomic hybridization. Among 54 intellectual disability trios selected from the previous cohort who were re-tested with 500 K GeneChip® array genomic hybridization, we identified all 10 previously-detected pathogenic genomic alterations and at least one additional pathogenic copy number variant that had not been detected with 100 K GeneChip® array genomic hybridization. Many benign copy number variants, including one that was de novo, were also detected with 500 K array genomic hybridization, but it was possible to distinguish the benign and pathogenic copy number variants with confidence in all but 3 (1.9%) of the 154 intellectual disability trios studied.ConclusionAffymetrix GeneChip® 500 K array genomic hybridization detected pathogenic genomic imbalance in 10 of 10 patients with idiopathic developmental disability in whom 100 K GeneChip® array genomic hybridization had found genomic imbalance, 1 of 44 patients in whom 100 K GeneChip® array genomic hybridization had found no abnormality, and 16 of 100 patients who had not previously been tested. Effective clinical interpretation of these studies requires considerable skill and experience.

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Section: Discussionmentioning

confidence: 99%

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

et al. 2009

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“…[7][8][9][10]59,[71][72][73][74][75] ). As a visual estimate, the detection rates in the validation and practice group are provided (gray background).…”

Section: Discussionmentioning

confidence: 99%

Addition of H19 ‘Loss of Methylation Testing’ for Beckwith-Wiedemann Syndrome (BWS) Increases the Diagnostic Yield

Lennerz

Timmerman

Grange

et al. 2010

The Journal of Molecular Diagnostics

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Beckwith-Wiedemann syndrome (BWS) is a clinical diagnosis; however , molecular confirmation via abnormal methylation of DMR2(LIT1) and/or DMR1(H19) has clinical utility due to epigenotype-tumor association. Despite the strong link between H19 hypermethylation and tumor risk, several diagnostic laboratories only test for hypomethylation of LIT1. We assessed the added diagnostic value of combined LIT1 and H19 testing in a large series of referred samples from 1298 patients, including 53 well-characterized patients from the St. Louis Children's Hospital BWS-Registry (validation samples) and 1245 consecutive nationwide referrals (practice samples). Methylation-sensitive enzymatic digestion with Southern hybridization assessed loss of normal imprinting. In the validation group, abnormal LIT1 hypomethylation was detected in 60% (32/52) of patients but LIT1/H19-combined testing was abnormal in 68% (36/53); sensitivity in the practice setting demonstrated 27% (342/1245) abnormal LIT1 and 32% (404/ 1245) abnormal LIT1/H19-combined. In addition, H19 methylation was abnormal in 7% of LIT1-normal patients. We observed absence of uniparental disomy (UPD) in 27% of combined LIT1/H19-abnormal samples, diagnostic of multilocus methylation abnormalities; in contrast to studies implicating that combined LIT1/H19 abnormalities are diagnostic of UPD. The overall low detection rate, even in validated patient samples and despite characterization of both loci and UPD status, emphasizes the importance of clinical diagnosis in

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“…This complexity can cause difficulty in obtaining a molecular diagnosis. Ten to twenty percent of patients with BWS have paternal uniparental disomy (UPD) (Cyntrynbaum et al ., 2005). The majority of these patients have segmental paternal UPD for 11p15, suggesting that there was a post-zygotic recombination that caused the mosaicism.…”

Section: Considerations In the Differential Diagnosismentioning

confidence: 99%

“…The imprinting defects in BWS have been well described by other authors and will not be discussed in detail here. (Cooper et al ., 2005; Bliek et al ., 2001; Weksberg et al ., 2001; Cytrynbaum et al ., 2005; Debaun et al ., 2003; Lam et al ., 1999). …”

Section: Considerations In the Differential Diagnosismentioning

confidence: 99%

Genetic considerations in the prenatal diagnosis of overgrowth syndromes

Vora

Bianchi

2009

Prenatal Diagnosis

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Large (>90%) for gestational age (LGA) fetuses are usually identified incidentally. Detection of the LGA fetus should first prompt the provider to rule out incorrect dates and maternal diabetes. Once this is done, consideration should be given to certain overgrowth syndromes, especially if anomalies are present. The overgrowth syndromes have significant clinical and molecular overlap, and are associated with developmental delay, tumors, and other anomalies. Although genetic causes of overgrowth are considered postnatally, they are infrequently diagnosed prenatally. Here, we review prenatal sonographic findings in fetal overgrowth syndromes, including Pallister-Killian, Beckwith-Wiedemann, Sotos, Perlman, and Simpson-Golabi-Behmel. We also discuss prenatal diagnosis options and recurrence risks.

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Advances in overgrowth syndromes: clinical classification to molecular delineation in Sotos syndrome and Beckwith-Wiedemann syndrome

Cited by 20 publications

References 49 publications

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

Addition of H19 ‘Loss of Methylation Testing’ for Beckwith-Wiedemann Syndrome (BWS) Increases the Diagnostic Yield

Genetic considerations in the prenatal diagnosis of overgrowth syndromes

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