Table 2.
Summary of cases with reported or possible diagnoses upon reanalysis.
| Case | Phenotype | Potential diagnostic gene (RefSeq transcript ID) | Potential diagnostic variant(s) | Zygosity (inheritance) | Potential diagnosis | Classification | Outcome (reason not reported) | Resultant changes in medical care | Changes between initial analysis and reanalysis |
|---|---|---|---|---|---|---|---|---|---|
| 6009 | Small for gestational age and failure to thrive, congenital heart defects, bilateral ectrodactyly | IGF2 (NM_001127598.1) | c.267C>A, p.(Cys89*) | Heterozygous (paternally phased de novo mutation) | Silver–Russell syndrome | P | Reported | Assessment of renal and hepatic function, blood pressure. Avoidance of metronizadole. Consideration of baclofen, carbidopa/levodopa | Correction of manual data labeling error. 2016 classification of this variant as pathogenic (GeneDx; ClinVar accession SCV000491643.1) |
| 6033 | Failure to thrive, intention tremor, ataxic gait, developmental regression, hypotonia, microcephaly, white matter abnormalities on MRI | ERCC6 (NM_000124.3) | c.-15+3G>T; c.1583G>A, p.(Gly528Glu) | Heterozygous (paternal); heterozygous (maternal) | Cockayne syndrome type B | P; LP (after orthogonal functional testing) | Reported | Growth hormone treatment, hypoglycemia prevention, monitoring for premature adrenarche, maxillofacial assessment | Publication of c.1583G>A variant in Cockayne syndrome cohort (Calmels et al.24). Research-basis functional testing of patient fibroblasts |
| 6046 | Unprovoked cardiac arrest, sudden infant death syndrome, suspicion of long Q-T syndrome | ANK2 (NM_001148.4) | c.1574C>T, p.(Ala525Val) | Heterozygous (maternal) | Long Q-T syndrome 4 | VUS; VUS | Queue for periodic reanalysis (VUS) | N/A | 2018 classification of this variant as a VUS in association with long Q-T syndrome (Invitae; ClinVar accession SCV000822853.1) |
| 6062 | Feeding difficulties, ketosis, mast cell activation disorder, hypotonia, joint hypermobility, fine motor delay, fatigue after exercise | GAA (NM_000152.4) | c.-32-13T>G; c.497C>T; p.(Thr166Ile) | Heterozygous (not maternal); heterozygous (maternal) | Glycogen storage disease II | P; VUS | Queue for periodic reanalysis (VUS, unclear phenotypic matching) | N/A | GAA variants reported to patient by GeneDx, following physician-requested analysis of clinical exome data for GSD genes. Subsequent functional testing of patient alpha glucosidase, with results in low-normal range |
| 6068 | Acute lymphoid leukemia in remission, rectal fistula, gallstones, fevers, clotting | JAK2 (NM_004972.3) | c.2600G>A, p.(Arg867Gln) | Unknown (parental samples unavailable) | Leukemia susceptibility (novel gene/disease association) | VUS | Queue for periodic reanalysis (VUS, unclear gene–disease relationship) | N/A | Publication of this variant segregating in a kindred with thrombocytosis and progression to polycythemia vera in one affected (Maie et al.25) |
| 6081 | Arthrogryposis multiplex congenita, micrognathia, desaturations, parenchymal dysplasia, cortical dysplasia, bilateral clubfeet, suspected congenital knee dislocation, uterine growth restriction | B3GALT6 (NM_080605.3) | c.122C>T, p.(Ala41Val); c.950C>T p.(Pro317Leu) | Heterozygous (maternal); heterozygous (paternal) | Ehlers–Danlos syndrome, spondylodysplastic type 2 | VUS; VUS | Queue for periodic reanalysis (VUS, unclear phenotypic matching) | N/A | — |
P Pathogenic, LP Likely Pathogenic, VUS Variant of Uncertain Significance.