Genetics

It is now well established that ACDMPV is a genetic disease, which means that ACDMPV occurs due to abnormalities in the DNA. However, this does not mean that ACDMPV is familial (i.e. hereditary or inherited) in most cases. In the majority of cases, the genetic abnormalities found in the ACDMPV affected child are not present in either of their parents and thus the risk of other children from the same parents being affected by ACDMPV is often low, subject to certain caveats further described below.

There are two broad types of genetic abnormalities that have been found to cause ACDMPV:

(1)    a mutation of the FOXF1 gene on chromosome 16; or
(2)   other genetic abnormalities such as deletions in the areas of chromosome 16 that regulate the expression of the FOXF1 gene.

When undertaking the genetic testing process, the following steps are typically followed:

Step 1: Mutation testing via FOXF1 gene sequencing. If a FOXF1 mutation is found in the ACDMPV affected child, then the parental samples are tested and (i) if a familial link is found, then the risk of recurrence is high, and (ii) if no familial link is found, then it is considered de novo and the risk of recurrence is lower around 1-2% (due to gonadal mosaicism, somatic mosaicism or an unknown gene, see further details below).

If no mutation is found via FOXF1 gene sequencing, then step 2 below.

Step 2: Deletion testing via microarray/CGH. If a deletion is found in the ACDMPV affected child, then the parental samples are tested and (i) if a familial link is found, then the risk of recurrence is high, and (ii) if no familial link is found, then it is considered de novo and the risk of recurrence is lower around 1-2% (due to gonadal mosaicism, somatic mosaicism or an unknown gene).

If no deletion is found via microarray/CGH, then step 3 below.

Step 3:  Whole exome testing if no mutation or deletion found above.


How do the genetics of ACDMPV work? The genetics of ACDMPV are complex and not fully understood at this time but progress is being made each year. New genetic abnormalities are being found regularly, but at present around 80-90% of infants with confirmed ACDMPV can be found to have one of the two types of abnormalities discussed above (i.e. a mutation or deletion). The genetic abnormalities responsible for ACDMPV in the remaining 10-20% of cases are currently being investigated, including testing for deletions farther away from the FOXF1 gene on chromosome 16 and whole exome testing.

In approximately 90% of cases of ACDMPV where a genetic abnormality has been found in the child, it appears to have arisen de novo (spontaneous) and is NOT inherited from a parent. Please keep in mind these additional caveats:

1. In rare cases a genetic abnormality found in the child was not detected in the parental blood sample but the family experienced a recurrence in a subsequent pregnancy. Baylor believes this rare circumstance could be caused by the presence of a gonadal mosaicism, which means there is a percentage of affected eggs in the mother’s ovary but such abnormality is limited to the eggs and not present in the mother’s DNA/blood. This is a rare occurrence but a risk to be kept in mind as prior testing of all the eggs via a traditional pregnancy is not possible.

2.  Somatic mosaicism describes the situation where an individual has more than one type of genetic material in their body (e.g. both normal and abnormal copies of a gene). This arises due to mutations as our cells divide. Conventional genetic tests often fail to find somatic mosaicism as it is often low-level (sometimes <1% of DNA) and thus extremely difficult to detect. Baylor routinely tests with PCR sensitivity for low-level somatic mosaicism in parents of ACDMPV infants with FOXF1 related deletions. Baylor has previously been unable to test for low-level somatic mosaicism in the parents of ACDMPV infants with a FOXF1 mutation due to unreliability of this test at such levels. However, Baylor has been working on a more sensitive method for mutation testing (approaching PCR sensitivity) and recently tested multiple parental samples for such low-level somatic mosaicism mutations. Please note Baylor has confirmed it will continue to conduct its remarkably sensitive testing capabilities for somatic mosaicism related to deletions but such testing may not regularly be available for somatic mosaicism related to mutations.

3.  Remember there are 10-20% of cases where neither a mutation nor a deletion was found in the ACDMPV affected child. Research is currently trying to determine the cause of ACDMPV in these cases (such as a deletion farther away than previously tested and whole exome testing). The ACDA is not currently aware of a case of recurrence in these type of cases but this does not conclusively mean that recurrence cannot happen.

Key takeaway –> This means that overall, considering familial ACDMPV, gonadal mosaicism and somatic mosaicism (each as discussed in the paragraphs above), the expected risk of having more than one child affected by ACDMPV is somewhere around 10% before testing parental blood samples. If it is determined neither parent carries the genetic abnormality in their blood samples, the risk of having more than one child with ACDMPV falls to 1-2% (due to gondadal mosaicism, somatic mosaicism or an unknown gene).

The best way to detect genetic abnormalities is using a blood sample from an infant. If this is not possible, DNA can also be extracted from a tissue sample, for example a lung biopsy or autopsy (post mortem). Note a blood sample for genetic testing can be collected either prior to or after an infant is placed on ECMO as the donor blood used for ECMO is depleted of the white blood cells that are used in genetic testing before it is given to the infant and therefore there is no chance of contamination.

If an ACDMPV affected child has a genetic abnormality detected, this can be used to test future siblings when the mother is pregnant (or after birth) to look for ACDMPV if so desired. DNA can be taken from the fetus when in the womb by one of two procedures known as chorionic villus sampling (CVS) and amniocentesis. This genetic testing is offered by the clinical diagnostic laboratories at Baylor College of Medicine.

Due to ongoing developments in ACDMPV research, the above genetic information is not to be relied upon as medical advice and should always be discussed and confirmed with your qualified geneticist or other trusted medical professional.  In addition, the ACDA encourages all genetic testing to be conducted or reviewed by Baylor College of Medicine in Houston, Texas, USA as Baylor uses sensitive testing capabilities not always available elsewhere.


Please click HERE to read a prior summary about the genetics of ACDMPV in 2015, written by Dr. Simon Ashwell and Professor Pawel Stankiewicz. This prior version includes a brief glossary of genetics.