Beckwith-Wiedemann syndrome: H19 & LIT1 methylation1

Test #:


Turnaround Time:

3-4 weeks

Specimen Requirements:

Specimens should be shipped at room temperature in a leak-proof, rigid container with overnight delivery. To discuss minimum acceptable specimens for neonatal patients or for sample types not listed, please contact Allele Diagnostics.

  • Peripheral whole blood in EDTA: 2-3 mL
CPT Codes:

81401 x1

Ordering Requirements:
Condition Description:

Beckwith-Wiedemann syndrome (BWS) is a growth disorder. Clinical features commonly include: macrosomia (large body size), macroglossia (enlarged tongue), visceromegaly, omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). Polyhydramnios may be identified during pregnancy. Infants with BWS have an approximately 20% mortality rate, mainly caused by complications of prematurity, omphalocele, and/or hypoglycemia. Macroglossia and macrosomia are generally present at birth but may have postnatal onset. The growth rate slows around seven to eight years of age. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues. In addition, individuals with BWS are at an increased risk of developing embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma). Development and intelligence are typically unaffected, with the exception of mild speech delay in some individuals with severe macroglossia.

Defects in imprinted gene expression at 11p15 are associated with BWS. Greater than 70% of cases are found to have alterations in DNA methylation at two distinct differentially methylated regions (DMRs) at 11p15. DMR1 is located within the telomeric domain (also known as ICR1) and controls the expression of two genes, IGF2 and H19. DMR2 is located within the centromeric domain (also known as ICR2) and controls the expression of the KCNQ1CDKN1CSLC22A1L and TSSC3 genes. Alterations in DNA methylation at either of these DMRs causes aberrant expression of these imprinted genes leading to Beckwith-Wiedemann syndrome.

BWS is typically sporadic, though inheritance has also been reported in an autosomal dominant pattern, due to other mutations. No single explanation can account for the phenotypic heterogeneity seen in patients with BWS. The recurrence risk due to methylation defects is estimated to be low.

Clinical Utility:
  • Individuals with a clinical diagnosis of Beckwith-Wiedemann syndrome.
  • Individuals with isolated segmental hemihyperplasia.
Genes (2):

H19, KCNQ1OT1 (LIT1)

Test Description:

Performed using methylation-specific MLPA (MS-MLPA).

One advantage of MS-MLPA is that in addition to detecting DNA methylation abnormalities (epimutations), similar to Southern blot and quantitative methylation sensitive PCR, it also detects deletions and duplications (CNVs) of the 11p15 region. CNVs are estimated to be present in ~10% of patients with BWS. The presence of a CNV can increase the recurrence risk from that of the general population up to a 50% risk. Both methylation and CNVs will be reported from this analysis.


For DMR1 (H19 gene), an increase in DNA methylation of greater than two standard deviations above the mean of normal is consistent with BWS. For DMR2 (LIT1 gene), a decrease in DNA methylation of greater than two standard deviations below the mean of normal is consistent with BWS. See Coffee et al. for explanation of reference range.

  • Coffee et al. Genet. Med. 2006: 8(10): 628-634.
  • Gaston et al. Eur J Hum Genet. 2001; 6:409-418.
  • Weksberg et al. Hum Mol Genet. 2003; 12: R61-68.
  1. This test is performed at a partner lab of Allele Diagnostics.