SNP = single nucleotide polymorphism; UPD = uniparental disomy

Proportion of affected individuals as classified by gene/locus, phenotype, population group, and/or test method, in individuals fulfilling clinical diagnostic criteria for BWS. Note: Frequencies may vary in different populations [Sasaki et al 2007].

Assays developed to be methylation sensitive (e.g., methylation-specific multiplex ligation-dependent probe amplification [MS-MLPA], quantitative PCR [MS-qPCR], Southern blotting) allow detection of epigenetic and genomic alterations of 11p15.5. Methylation-sensitive assays can discern microdeletions and microduplications, DNA methylation alterations, and uniparental disomy (UPD). Interpretation of methylation data should take into account results of karyotype analysis because karyotypic abnormalities that alter the relative dosage of parental contributions (e.g., paternal duplication) are associated with abnormal methylation status. Other methods to confirm UPD at 11p15.5 include short tandem repeat (STR) analysis or SNP analysis [Keren et al 2013].

Altered methylation at imprinted loci outside of 11p15.5 can be detected in approximately 30%-50% of individuals with BWS and loss of methylation at IC2. This condition is termed multilocus imprinting disturbance (MLID) and is more common in females (4:1 female-to-male ratio) [Sanchez-Delgado et al 2016, Fontana et al 2018, Tannorella et al 2022] (see Differential Diagnosis).

If the affected individual is found to have altered methylation at imprinted loci outside of 11p15.5, they may have MLID, for which further genetic testing may be entertained (see Differential Diagnosis).

Bliek et al [2001], Weksberg et al [2001]

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Some pathogenic variants may be missed on targeted sequencing and/or deletion/duplication testing and newer sequencing technologies (e.g., whole-genome sequencing) may be able to detect these.

The detection rate for CDKN1C sequencing varies by family history [Hatada et al 1997, Lee et al 1997, O'Keefe et al 1997, Lam et al 1999, Algar et al 2000, Li et al 2001, Brioude et al 2015].

Slavotinek et al [1997], Li et al [1998]

Paternal UPD occurs by postzygotic somatic recombination and can, therefore, be identified by proband-only SNP array analysis.

Many small chromosomal deletions, small chromosomal duplications, and UPDs are not detected by current microarray testing on the proband. These require high-density SNP arrays for detection.