Genomic and data checks¶
As part of the data quality processes followed in the genomic data analysis pipeline, comparisons are made between the pedigree and clinical data supplied and the corresponding information inferred from the genomic sequencing data, particularly to confirm that the sex and family relationships are as expected. These checks are performed by calculating the relative coverage of the sex chromosomes, identity by descent genotype sharing between family members and the number of mendelian inconsistencies per chromosome (where appropriate).
In the test order system, there are 3 relevant fields relating to the reported sex:
| Field | Mandatory | Description |
|---|---|---|
| Gender |  |
Used to infer phenotypic sex if other fields left blank |
| Phenotypic sex | Should be completed if different from gender | |
| Karyotypic sex | Should be completed if unusual or discordant from phenotypic sex or gender |
In some cases where discrepancies are observed between the reported sex(es) and that inferred from the genomic data, data will pass through the Genomics England Interpretation Pipeline and a flag will be displayed in the Interpretation Portal (see Referral Flags). A separate flag will be displayed if a sex chromosome aneuploidy (also known as minor sex karyotype) is predicted from the genomic data.
Since the DRAGEN algorithms utilise the expected ploidy of the X and Y chromosomes (based on the inferred sex karyotype) in variant detection, erroneous genotypes for variants on the sex chromosomes may be observed for individuals with some minor sex karyotypes and tiering of variants on the X chromosome may be compromised (see Small Variant Tiering). The reported and inferred sex for each individual is displayed in the Interpretation Portal, along with the number of X chromosomes used for analysis. If further detail is required for a specific flagged case, a Jira service desk ticket should be raised by NHS GLH staff and a response will be provided by nhs.net email to an approved recipient. GLH staff may be contacted in the rare event that the inferred sex karyotype is ambiguous.
| Flag | Description |
|---|---|
| UNUSUAL SEX KARYOTYPE | Applies when at least one member of the family has a sex karyotype that is not XX or XY |
| INCORRECT OR DISCORDANT SEX KARYOTYPE | Applies when the reported karyotypic and phenotypic sex or gender are discrepant but the karyotypic sex is supported by the sex inferred from the genomic data |
| INFERRED GENETIC AND REPORTED SEX DISCORDANT | Applies when the reported sex is discrepant from the inferred genetic sex and the Disorders of Sexual Development panel has been applied, or the GLH has confirmed that the discordance is not due to a data entry error |
| UNKNOWN PHENOTYPIC SEX | Applies when at least one member of a family has an unknown phenotypic sex |
If there is discrepancy between the reported sex and the inferred genetic sex and the Disorders of Sex Development panel has not been applied, queries will be raised with NHS GLHs to confirm or correct the phenotypic information prior to the sample proceeding through the interpretation pipeline.
Queries may also be raised when the expected relationships between family members are not supported by the genomic data. These queries will be returned in the DQ report (and in future in the MI portal). In the event of a complex inconsistency, such as a sex discrepancy or misattributed relationship, the DQ report will indicate only the query category and specific details will be sent by nhs.net email to a nominated address.