Table 2.
Reported secondary findings in our cohort.
| Case no. | Fetal phenotype | Gene and reference sequence | Identified variant | Disorder | Disorder inheritance, variant zygosity and origin | ACMG classification/criteria** | Novel/known variant | ClinVar ID |
|---|---|---|---|---|---|---|---|---|
| 6* | NT > 7 mm, heart defect, multicystic dysplastic kidneys, shortened long bones, bilateral clubfoot, abnormal skull configuration |
SBDS NM_016038.2 |
c.258+2T>C, p.(?) | Shwachman-Diamond syndrome |
AR, hom, mother also homozygous, father heterozygous (parents are consanguineous) |
5 | Known | VCV000003196.14 |
| 8* | Skeletal dysplasia, IUGR (length of long bones and fetal weight < 3rd percentile, small thorax) |
KMT2D NM_003482.3 |
c.5468-1G>A, p.(?) | Kabuki syndrome 1 |
AD, het, maternally inherited |
5 PVS1/PM2-M/PP3-S |
Novel | SCV001519078 |
| 20 | Microcephaly, agenesis of right kidney |
BRCA2 NM_000059.3 |
c.7350_7354del, p.(Asn2450Lysfs*2) |
Breast-ovarian cancer, familial, 2 |
AD, het, paternally inherited |
5 PP5-VS/PVS1/PM2-M |
Known | VCV000254601.2 |
|
DUOX2 NM_014080.4 |
c.605_621del, p.(Gln202Argfs*93) | Thyroid dyshormonogenesis 6 | AR, hom | 5 | Known | SCV001519079 |
In all listed fetuses a diagnostic variant of underlying malformation has been identified.
*Tested with a panel encompassing 6713 genes.
NT nuchal translucency, IUGR intrauterine growth retardation, AD autosomal-dominant inheritance, AR autosomal recessive inheritance, Hom homozygous, Het heterozygous, ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/.
**ACMG criteria are listed only for novel variants, ACMG variant classification [15] (5 = pathogenic, 4 = likely pathogenic, 3 = variant of unknown significance, 2 = likely benign, 1 = benign); variants are described according to HGVS nomenclature.
There are no corresponding identifiers to patient numbers.
ACMG criterion applied:
PVS1: Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease.
PM2-M: Absent from controls in gnomAD database, used at a moderate level.
PP3-S: Multiple lines of computational evidence support a deleterious effect on the gene or gene product, used at the supporting level.
PP5-VS: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation, used at a very strong level.