Table 12. [Risk to Offspring of a Proband with Beckwith-Wiedemann Syndrome]. - GeneReviews®

Genetic Alteration Identified in the Proband	Recurrence Risk to Offspring of the Proband
Abnormal methylation at 11p15.5	LOM at IC2 or GOM at IC1	Likely low unless the proband is female and presents with a history of unexplained spontaneous abortion, hydatidiform moles, or a sib w/BWS or another imprinting disorder (e.g., SRS); in such cases, a homozygous or heterozygous pathogenic variant in maternal effect genes in the proband’s genome may confer a significant recurrence risk (see Differential Diagnosis, MLID).
Genomic variant involving chromosome 11p15.5; incl: Cytogenetically visible duplication, inversion, or translocations CNV (e.g., small 11p15.5 duplication or deletion)	The recurrence risk may be as high as 50% depending on the sex of the proband and the specific alteration. Small deletions at IC1 & rarely small duplications at IC2 have been reported in familial cases. ¹ Rare familial cases of SRS (see Genetically Related Disorders) have been reported in persons w/small 11p15.5 IC1 deletions & maternally inherited 11p15 duplications. Therefore, the offspring of a proband w/either of these genetic alterations may be at risk for SRS depending on the specific alteration & the sex of the proband.
Paternal UPD of 11p15.5	Likely very low; however, empiric data are not yet available.
No underlying 11p15.5 genetic alteration identified in the proband	Presumed to be low in the absence of a genomic abnormality, as the imprint normally is reset in the germline; empiric data are not yet available. ² There remains a low risk for unidentified molecular alterations or MLID (see Differential Diagnosis, MLID).
Heterozygous CDKN1C pathogenic variant	If the proband is female, the recurrence risk for BWS in offspring is 50%.
If the proband is male, the recurrence risk for BWS in offspring is low, but there have been too few cases reported to generate a risk figure.
No BWS-causing genetic alteration identified in the proband (~20% of probands w/BWS do not have a molecular diagnosis.)	The recurrence risk is likely low as the proband may have somatic mosaicism for paternal UPD. However, the risk may be increased if the proband has a pathogenic variant that is not detected by current genetic testing platforms or (in a female proband) a pathogenic variant(s) in an SCMC gene.

Genetic Alteration Identified in the Proband

Recurrence Risk to Offspring of the Proband

Abnormal methylation at 11p15.5

LOM at IC2 or GOM at IC1

Likely low unless the proband is female and presents with a history of unexplained spontaneous abortion, hydatidiform moles, or a sib w/BWS or another imprinting disorder (e.g., SRS); in such cases, a homozygous or heterozygous pathogenic variant in maternal effect genes in the proband’s genome may confer a significant recurrence risk (see Differential Diagnosis, MLID).

Genomic variant involving chromosome 11p15.5; incl:

Cytogenetically visible duplication, inversion, or translocations
CNV (e.g., small 11p15.5 duplication or deletion)

The recurrence risk may be as high as 50% depending on the sex of the proband and the specific alteration. Small deletions at IC1 & rarely small duplications at IC2 have been reported in familial cases. ¹
Rare familial cases of SRS (see Genetically Related Disorders) have been reported in persons w/small 11p15.5 IC1 deletions & maternally inherited 11p15 duplications. Therefore, the offspring of a proband w/either of these genetic alterations may be at risk for SRS depending on the specific alteration & the sex of the proband.

Paternal UPD of 11p15.5

Likely very low; however, empiric data are not yet available.

No underlying 11p15.5 genetic alteration identified in the proband

Presumed to be low in the absence of a genomic abnormality, as the imprint normally is reset in the germline; empiric data are not yet available. ² There remains a low risk for unidentified molecular alterations or MLID (see Differential Diagnosis, MLID).

Heterozygous CDKN1C pathogenic variant

If the proband is female, the recurrence risk for BWS in offspring is 50%.

If the proband is male, the recurrence risk for BWS in offspring is low, but there have been too few cases reported to generate a risk figure.

No BWS-causing genetic alteration identified in the proband (~20% of probands w/BWS do not have a molecular diagnosis.)

The recurrence risk is likely low as the proband may have somatic mosaicism for paternal UPD. However, the risk may be increased if the proband has a pathogenic variant that is not detected by current genetic testing platforms or (in a female proband) a pathogenic variant(s) in an SCMC gene.

From: Beckwith-Wiedemann Syndrome

GeneReviews^® [Internet].

Adam MP, Feldman J, Mirzaa GM, et al., editors.

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