Table 1.
Influence of post-exome review of WES reports by clinical geneticist
| ID | Sex | Singleton or Trio | Gene | Variants reclassified/ discovered | Inheritance | Case-level classification | Clinical-level classification | Change in classification | Description | I. Post-exome phenotyping | II. Post-exome diagnostics | III. Extensive database evaluation | IV. Expert liaison | V. Clinical functional assay |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| U023 | F | Singleton | UPB1 | c.977G>A(p.Arg326Gln) Hom | AR (Inherited) | Candidate | Definitive | Promoted | Initially thought to be a VUS due to relatively high MAF in East Asians. The variant has been subsequently reported multiple times in the Chinese and Japanese populations. Discussion with experts and testing urine for purines and pyrimidines confirmed the diagnosis. | ● | ● | ● | ||
| U024 | F | Singleton | MECP2 | c.1126C>T (p.Pro376Ser) Het | AD (inherited) | Possible | Unlikely | Demoted | First reported to be a possible cause, review of Rett disease-specific database showed that this was more likely a common benign polymorphism. | ● | ||||
| U027 | M | Singleton | SBDS | c.184A>T(p.Lys62*); c.258+2T>C (r.spl?) Het |
AR (Inherited) | Candidate | Definitive | Promoted | A VUS in the GRIN2A gene was initially ruled out after discussion with experts. This was communicated back to the laboratory and further mutations in SBDS were revealed. These were not included in the initial report as WES was unable to separate the normal gene from pseudogene with 97% homology. By obtaining specific primers from experts, the diagnosis was confirmed. | ● | ● | |||
| U028 | M | Singleton | COQ4 | c.402+1G>A Het; c.550T>C (p.Trp184Arg) Het |
AR (Inherited) | Possible | Definitive | Promoted | Functional testing for COQ4 enzyme essay was arranged to confirm the pathogenicity of a VUS (c.550T>C). | ● | ● | |||
| U029 | M | Singleton | SPAST | c.1045T>G (p.Leu349Val) Het c.1824C>G (p.Asn608Lys) Het |
AR (Inherited) | Candidate | Unlikely | Demoted | Further clinical samples from family members and consultation of expert groups demoted this to a likely benign variant. | ● | ● | |||
| U031 | F | Singleton | PIGO | c.2191del (p.Arg731fs) Het c.458T>C (p.Phe153Ser) Het |
AR (Inherited) | Possible | Definitive | Promoted | Atypical presentation of this patient with normal Alkaline phosphatase required expert liaison and further functional studies by flow cytometry to confirm the diagnosis. | ● | ● | ● | ||
| U033 | F | Singleton | SLC35A2 | c.569dup (p.Gly191fs) Het | XL (de novo) | Possible | Definitive | Promoted | Consultation of expert groups, X-inactivation studies and transferrin electrophoresis was arranged to confirm the pathogenicity of this previously unreported variant. | ● | ● | |||
| U039 | F | Singleton | NF1 | c.2970_2972del (p.Met992del) Het | AD (de novo) | Possible | Definitive | Additional Finding | Although the patient phenotype was consistent with a variant in CREBBP, the finding of café au lait spots on examination prompted reanalysis for an additional NF1 variant. | ● | ||||
| U049 | M | Singleton | ATP6V1A | c.215G>A (p.Gly72Asp) Hom | AR (inherited) | Candidate | Definitive | Promoted | Collaboration with expert groups allowed complex functional studies and discovery of this new disease gene ATP6V1A. | ● | ● | ● | ||
| U051 | M | Singleton | COL6A2 | c.1358G>A (p.Arg453His) c.1706G>A (p.Arg569Gln) c.3003C>A (p.Asp1001Glu) |
AD/AR (n/a) | Candidate | Unlikely | Demoted | Consultation of an international expert confirmed that the candidate gene did not fit with the known phenotype. | ● | ||||
| U068 | M | Singleton | CSNK2A1 | c.593A>G (p.Lys198Arg) | AD (de novo) | Candidate | Definitive | Promoted | On initial report, this variant has not been reported before, but several other similar cases were identified by the WES laboratory. Collaboration to aggregate cases resulted in a publication (Chiu et al. 2018). | ● | ● | |||
| U070 | M | Singleton | GJB2 | c.109G>A (p.Val37Ile) Hom | AR (inherited) | Definitive | Unlikely | Demoted | Discussion with various groups demoted this variant of variable expressivity and penetrance to a VUS. | ● | ||||
| U096 | F | Singleton | ABCB11 | c.3429C>G (p.Asp1143Glu) c.2594C>T (p.Ala865Val) |
AR (inherited) | Possible | Unlikely | Demoted | Phenotype correlation and review of local databases demoted this to an unlikely diagnosis. | ● | ● | |||
| U098 | M | Singleton | IGHMBP2 | c.2356del (p.Ala786fs) c.905_912+83del |
AR (inherited) | Candidate | Definitive | Additional Finding | Liaison with laboratory facilitated reanalysis of exome data and discovery of an additional 83 bp deletion in an AR disease. | ● | ||||
| U003 | M | Trios | ATRX | c.740A>G (p.Asn247Ser) | XL (inherited) | Possible | Definitive | Promoted | Atypical presentation at 4 months old with no suggestion of alph-thalassemia or intellectual disability, review and follow-up of patient found low MCV on CBP and developmental delay, arranging a test for Hb H inclusion bodies confirmed the diagnosis. | ● | ||||
| U030 | M | Trios | ARID1A | c.3406G>A (p.Ala1136Thr) | AD (de novo) | Candidate | Definitive | Promoted | Originally reported as a novel variant of unknown significance. Further review of the phenotype and literature was required to confirm the diagnosis. | ● | ● | |||
| U103 | M | Trios | FGD1 | exon 5 deletion | XL (inherited) | Negative | Definitive | Additional Finding | Exome report was initially negative i.e. no candidate variants identified. Expert opinion suggested targeted analysis of genes for Robinow syndrome and Aarskog–Scott syndrome was performed, for which no mutations were found on initial WES report. Further discussion with the exome laboratory identified low coverage areas in the FGD1 gene, and a deletion was identified by MLPA. | ● | ● | |||
| 5 | 7 | 5 | 11 | 3 |
Post-exome review of WES reports led to a more comprehensive assessment in 16 cases. One additional finding (U103) was discovered by reanalysis of a negative report