The Exeter Genomics Laboratory is offering bespoke noninvasive prenatal testing in pregnancies at risk of monogenic diabetes where knowledge of fetal genotype will impact pregnancy management, delivery and immediate postnatal care.
How could this test be helpful?
In pregnancies affected by GCK-MODY:
If the baby inherits the maternal GCK variant – the baby would be expected to have a normal birthweight as per background population (Hattersley et al., 1998 PMID:9662401; Spyer et al., 2009 PMID: 19125755).
We do not recommend treatment of maternal hyperglycaemia, as the baby would not be expected to have a higher risk of being born large-for-gestational-age than the background population (Hattersley et al., 1998 PMID:9662401; Spyer et al., 2009 PMID:19125755).
If the baby does not inherit the maternal GCK variant – it would have a higher risk of macrosomia / large-for-gestational age (~800g increase in birth weight).
Optimal management is not established in this situation. When the baby is unaffected treatment for maternal hyperglycaemia with insulin is routinely recommended in the last trimester of pregnancy (Chakera et al 2015 PMID: 26106223) to try to limit fetal growth. However in GCK patients insulin has very little impact on blood glucose as their glucose is regulated at the high fasting level and they counter regulate when the glucose reaches normal (target) glucose levels (Chakera et al 2018 PMID: 30146176). In a large series the corrected birth weight of unaffected offspring was no different in those treated with insulin and those not treated/ diet treated (Spyer 2009 PMID: 19125755). We would recommend monitoring of fetal growth with ultrasound (28, 32, 36 weeks) and planning a delivery at 37-39 weeks gestation. Insulin treatment should be considered for the pregnant women, though high doses can be needed and can result in hypoglycaemic symptoms when trying to achieve pregnancy targets.
In pregnancies affected by HNF4A-MODY
A baby which inherits a HNF4A variant from either parent is at increased risk of macrosomia (~mean increase in birth weight of 800g) and of neonatal hyperinsulinaemic hypoglycaemia (in about 10%). (Pearson et al 2007 PMID: 17407387).
If the mother passes on the HNF4A variant – maternal hyperglycaemia results in an additional increase in birth weight on top of the direct effect of the HNF4A genetic change in the baby. We recommend tight glucose control; delivery at 37 weeks, or even pre-term; and close neonatal monitoring of glucose (involve the neonatologists before delivery).
If the father passes on the HNF4A variant – we recommend monitoring of fetal growth with ultrasound (28, 32, 36 weeks); consideration of planned delivery before the due date; and close neonatal monitoring of glucose (involve the neonatologists before delivery).
When should I request this testing?
Testing should be discussed in advance or as soon as the patient has a confirmed pregnancy to ensure that necessary samples and validation work can be performed in time to help with the management of the pregnancy. This NIPD service is only available for certain variant types – please contact the laboratory for further information.
For women that present pregnant, or are diagnosed with monogenic diabetes in pregnancy, this discussion should take place as soon as possible after the 12-week scan confirms a viable pregnancy.
What samples are required?
- Maternal venous blood samples collected in specialised StreckTM tubes (three tubes required) which stabilise the cell free DNA and;
- a fingerprick capillary blood sample from the father of the baby;
- a cord blood sample when the baby is born.
A pack containing the maternal and paternal blood collection kits will be sent once we have confirmed that testing is possible; if the genetic diagnosis was made at a different laboratory, we will also need control genomic DNA extracted from EDTA whole blood from the index case.
Why do you need a sample from the father of the baby?
This NIPD test relies on the paternal sample to determine the amount of fetal DNA that is present in the cell free DNA sample. We look for an “informative SNP” which is an area of the DNA which is present in the father and not the mother. We are working on methods to avoid needing a paternal sample in the future.
Why do you need a cord blood sample of the baby?
This it needed to confirm the diagnosis in the baby once it is born.
How accurate is the test?
For our GCK-MODY pregnancies, in a direct comparison with fetal abdominal circumference on ultrasound, (n=38 pregnancies with this available), we observed a sensitivity of 100%, specificity of 96%, positive predictive value of 94% and negative predictive value 100%. This is compared to the current recommended practice of a fetal abdominal circumference threshold of the 75th percentile, where sensitivity was 53%, specificity 61%, positive predictive value 47% and negative predictive value 67%. This data is currently in the process of being submitted for publication.
What is the reporting time for this test?
Because the test is bespoke for each family, it needs to be validated for each individual’s variant.
Results for assay validation are normally available within 3-4 weeks of sample receipt.
Results for the non-invasive prenatal test are normally available within 2 weeks.
Can the test identify a pathogenic variant that is known to cause a different disease?
The test and methodology will only look for the presence of the familial monogenic diabetes variant. No other analysis will be performed.
How do I get hold of the request forms and kits?
If this test is suitable for the patient then we will send out the kit and request forms. The kit contains the StreckTM blood collection tubes for the maternal blood samples and our at-home blood capillary kit for the paternal sample. We can send the kit directly to the patient or to a clinician.
The maternal blood samples can be taken by any trained healthcare professional. The blood capillary sample can be done by the father of the baby at home. The cord blood sample from the baby following delivery to confirm the non invasive result can be taken by a midwife or Obstetrician.
All samples must be labelled clearly with the individuals details and the provided request form completed. Any unlabelled samples will be not be tested. For UK referrals we provide pre-paid envelopes for you to return the samples back to us.
Why might you need a repeat sample?
It is not unusual to need additional samples, taken later in pregnancy, to get an accurate result. The original maternal sample may not have enough fetal DNA or the mother’s cells may lyse (break down), causing contamination of the fetal DNA with maternal genomic DNA and making it impossible to provide a result.
If there is enough time left in the pregnancy to process the test we will request additional maternal samples and send a new test kit.
How much does it cost?
This is an NHS England commissioned genomic test (R433) and the cost of the testing is therefore centrally funded for NHSE patients. We do accept non-NHSE referrals but because the monogenic diabetes NIPD testing is bespoke for each family, the current cost is £2050GBP (which includes £1200 for the assay validation and £850 for the test). For subsequent pregnancies you would only be charged for the test.
Where can I find more technical information about the test?
Non-invasive fetal genotyping by Droplet Digital PCR to Identify Maternally Inherited Monogenic Diabetes Variants. Caswell, R.C, Snowsill, T., Houghton, J.A.L., Chakera A.J., Shepherd, M.H., Laver, T.W., Knight, B.A., Wright, D., Hattersley, A.T., Ellard, S. Clin Chem 2020 1;66(7):958-965 PMID:32533152 https://pubmed.ncbi.nlm.nih.gov/32533152/
Analysis of cell-free fetal DNA for non-invasive prenatal diagnosis in a family with neonatal diabetes. De Franco E., Caswell R., Houghton JAL., Iotova V., Hattersley AT, Ellard S. Diabet Med. 2017 34(4):582-585 PMID: 27477181 https://pubmed.ncbi.nlm.nih.gov/27477181/
Where can I find clinical information about the management of GCK and HNF4A pregnancies?
