Beckwith-Wiedemann syndrome: H19 & LIT1 methylation¹

Test #:

8115

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:

• Pediatric Molecular Genetics Test Requisition Form
• Please include clinical notes and pedigree.

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 KCNQ1, CDKN1C, SLC22A1L 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.

Russell-Silver syndrome (RSS) is a rare growth disorder, typically characterized by asymetrical gestational growth restriction. At birth, individuals can be small for gestational age with relative macrocephaly, a promininent forehead with frontal bossing, and body asymmetry. Postnatally, individuals with RSS can show growth failure, progressive limb length discrepancy, and feeding difficulties. Characteristic dysmorphic features include triangular facies, fifth-finger clinodactyly, and micrognathia with chin narrowing. Less commonly observed clinical features include cafe-au-lait spots, genitourinary anomalies, motor/speech/cognitive delays, and hypoglycemia.

Hypomethylation of ICR1 at 11p15.5 causes RSS in 35-50% of individuals, and maternal uniparental disomy (mUPD7) causes RSS in 7-10% of individuals. There are a small number of individuals with RSS who have duplications, deletions, or translocations involving the imprinting centers at 11p15.5 or chromosome 7. Rarely, affected individuals with pathogenic variants in CDKN1C, IGF2, PLAG1, and HMGA2 have been described. Only 60% of individuals with a clinical diagnosis of RSS will have a detectable genetic variant. 

Like BWS, RSS is typically sporadic, though inheritance has also been reported in an autosomal dominant pattern, due to sequence variants. No single explanation can account for the phenotypic heterogeneity seen in patients with RSS. 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.
• Individuals with a clinical diagnosis or suspected clinical diagnosis of Russell-Silver syndrome.

Genes (2):

H19, KCNQ1OT1 (LIT1)

Test Description:

MS-MLPA

Methylation-sensitive multiple ligation-dependent probe amplification (MS-MLPA) is utilized to test for the presence of large deletions, duplications, and methylation defects in the IC1 (H19) and IC2 (LIT1) critical regions on chromosome 11p15.

Detection:

While testing can determine methylation status, it does not identify the mechanism responsible for the methylation defect (such as paternal/maternal uniparental disomy or cytogenetic abnormalities such as translocations or inversions). 

This assay does not detect maternal uniparental disomy of chromosome 7. 

References:

• 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.