Elsie's Story: How genomics can transform life before birth

This real life story is about a young family I recruited to the ground-breaking proof of concept 100,000 Genomes Project four years ago, and how through genomic sequencing, they were able to find out a genetic cause for their firstborn Elsie, who tragically died and how through genomics they were able to avoid further harm in future pregnancies. This story has been retold in a number of conferences and webinars such as "Niche to Necessity: Genomics in Routine Care" (webinar 2), with kind permission of Emily and Phil Gregson.

Emily, at 34 weeks pregnant was referred from her local hospital to Liverpool Women's Hospital (LWH), an inner-city tertiary level maternity service as an emergency transfer. Her baby had become less active and the cardiograph (CTG) which monitors the baby's heart and movements was abnormal. Emily underwent an emergency caesarean section and baby Elsie was immediately placed on assisted ventilation because she couldn't breathe on her own or move her limbs and moved to neonatal intensive care unit (NICU). The consultant paediatrician caring for Elsie was baffled.

Whilst standard NHS genetic testing was undertaken, the consultant suggested that Emily and her husband Phil think about joining the 100,000 Genomes Project as this may find a genetic diagnosis beyond the capabilities of the NHS tests. I met Emily and Phil on NICU and discussed the project with them and a few days later they made the decision to join the project. Upon receiving their verbal and written consent, blood samples were taken from Emily, Phil and Elsie and sent to Genomics England for whole genome sequencing (WGS).

Four weeks after recruiting the family to the Project, Elsie’s condition deteriorated, and a decision was made to turn off her life support.

Results eventually came back from the 100,000 Genomes Project which revealed the cause of Elsie's life-limiting condition. Elsie had inherited an autosomal recessive neurodegenerative incurable condition because of a variant or alteration within the ‘tubulin-specific chaperone D’ (TBCD) gene, located on chromosome 7. Unfortunately, Elsie received two altered copies of the TBCD gene: an altered copy from Emily, and an altered copy from Phil. Together, the two alterations sealed her fate.

Through the project, the pattern of inheritance enabled Emily and Phil to understand how and why this tragedy happened but provided them with choices for future pregnancies where they knew they faced in each pregnancy a:

• 1 in 4 chance of an unaffected child
• 2 in 4 chance the child is a ‘carrier’ (like them)
• 1 in 4 chance of an affected child

A year later, Emily and Phil were pregnant again with their second child. Placental tissue taken from a chorionic villus sampling (CVS), was analysed by the molecular genetics laboratory to check for alterations within the TBCD gene. The laboratory found the gene had no changes. Nine months later, baby Beatrice was born healthy and well and not a carrier (like her parents) for the gene.

Following Beatrice, the couple went on to have Ted. CVS performed during Ted’s development revealed that like Emily and Phil he carries an inherited healthy gene and a an altered TBCD gene. As a carrier, Ted is healthy and well but has the potential as an adult, to pass on his altered gene to his offspring.