Table 2 Consensus recommendations of the molecular working group
R | Recommendation | Strength of recommendation |
|---|---|---|
Molecular genetic analysis | ||
7 | Molecular genetic testing should be performed by a health professional experienced in the field of imprinting disorders. Recommended nomenclature (for example, HGVS) should be adopted in publications and in test reporting | A+++ |
8 | The flowchart outlined in Fig. 2 should be followed for molecular diagnosis of BWSp | A+++ |
9 | First-line molecular testing should include DNA methylation analysis of the H19/IGF2:IG DMR (IC1) and KCNQ1OT1:TSS DMR (IC2) regions. If a DNA methylation defect at either or both DMRs is found, further tests should be performed to identify possible underlying CNV or upd(11)pat (if it was not discriminated in initial diagnostic testing) | A+++ |
10 | Given the different tumour spectrum associated with mosaic genome-wide paternal uniparental disomy, further testing should be considered to distinguish this condition from upd(11)pat | A+++ |
11 | Detailed analysis of the H19/IGF2:IG DMR should be considered in individuals with GOM of this region, as SNVs and/or small CNVs can occur in these patients and confer high risk of recurrence (prioritized in the presence of a positive family history) | A+++ |
12 | In patients with a negative methylation test result, second-line molecular testing should be considered and might include sequencing of the coding exons and the exon–intron boundaries of CDKN1C (prioritized in the presence of a positive family history, a cleft palate or an abdominal wall defect (umbilical hernia or exomphalos)) | A+++ |
13 | In patients with a negative methylation test result, second-line molecular testing should be considered and might include analysis of additional tissues to detect somatic mosaicism (prioritized in the presence of asymmetric overgrowth) | A+++ |
14 | In patients with a negative methylation test result, second-line molecular testing should be considered and might include further tests for rare chromosomal rearrangements | A+++ |
15 | In patients with a negative methylation test result, second-line molecular testing should be considered, and might include re-evaluation of the clinical diagnosis and reconsideration of differential diagnoses | A+++ |
16 | Genetic counselling should be performed by a health professional experienced in the field of imprinting disorders | A+++ |
17 | As the recurrence risk associated with genetic defects (for example, CDKN1C loss of function variants, CNVs and DMR SNVs) is dependent on their size, location and parental origin, these factors should be taken into consideration during counselling for the family | A+++ |
Prenatal molecular genetic analysis | ||
18 | Prenatal molecular diagnostic investigations should be considered if prenatal ultrasonography reveals potential features of BWSp and should lead to a specific diagnosis (or exclude other potential conditions); they should also be considered if a positive family history with a known molecular defect is present, which would influence the management of the relevant pregnancy | A+++ |
19 | The flowchart indicated for postnatal testing (Fig. 2) is not necessarily applicable to prenatal testing. Modification of this flowchart depends on the individual setting (for example, known molecular defects and specific clinical features) | A+++ |
20 | Prior to offering prenatal diagnosis for BWSp, a detailed discussion of the technological limitations and ethical issues should be undertaken with the parents; in particular, they should be made aware that a normal result does not necessarily exclude the diagnosis | A+++ |
21 | It is recommended that centres offering prenatal diagnosis prospectively collect information on the true/false positive/negative diagnostic rates and that this information is contributed to multicentre audits to enable best practice guidelines to be further developed and refined | A+++ |
