Table 11.

Risk to Sibs of a Proband with Beckwith-Wiedemann Syndrome

Genetic Alteration Identified in the ProbandRecurrence Risk to Sibs of the Proband
Abnormal methylation at 11p15.5LOM at IC2 or GOM at IC1Empirically low unless there is a maternal 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 mother's genome may confer a significant recurrence risk (see Differential Diagnosis, MLID). 1
Genomic variant involving chromosome 11p15.5; incl:
  • Cytogenetically visible duplication, inversion, or translocation
  • CNV (e.g., small 11p15.5 duplication or deletion)
If a parent has the same genomic abnormality or is a carrier of a balanced chromosome rearrangement, the recurrence risk may be as high as 50% depending on the sex of the transmitting parent & the specific alteration.
Paternal UPD of 11p15.5Empirically low but not quantified 2
No underlying 11p15.5 genetic alteration identified in the proband
Heterozygous CDKN1C pathogenic variantIf the mother of the proband is heterozygous for the CDKN1C pathogenic variant identified in the proband, the recurrence risk for BWS in sibs is 50%. 3
If the mother is not heterozygous for the CDKN1C pathogenic variant identified in the proband, the risk to sibs of BWS is presumed to be low, but increased over that of the general population because of the possibility of maternal germline mosaicism. 4
No BWS-causing genetic alteration identified in the proband (~20% of probands w/BWS do not have a molecular diagnosis.)A genetic alteration may not be identified in the proband due to somatic mosaicism or to limitations in current genetic testing platforms. In the absence of a suggestive family history, the recurrence risk to sibs is empirically low but not quantified.

BWS = Beckwith-Wiedemann syndrome; CNV = copy number variant; GOM = gain of methylation; IC1 = imprinting center 1; IC2 = imprinting center 2; LOM = loss of methylation; MLID = multilocus imprinting disturbances; SRS = Silver-Russell syndrome; UPD = uniparental disomy

1.
2.
3.

If the father is heterozygous for the CDKN1C pathogenic variant, sibs have a 50% likelihood of inheriting the variant. The BWS recurrence risk in sibs who inherit a paternal CDKN1C pathogenic variant is increased but the exact risk is unknown. Unexpectedly, one instance of paternal transmission of a CDKN1C pathogenic variant from a clinically unaffected father has also been reported [Lee et al 1997, Li et al 2001].

4.

From: Beckwith-Wiedemann Syndrome

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