Genetics

Disclaimer:  The information provided below is a layperson summary for general knowledge only and is not intended or implied to be a substitute for advice or counseling from a qualified geneticist in a professional setting. This information should only be used as a starting point in developing your discussion with your qualified geneticist or other trusted medical professional. Please always consult your qualified geneticist with any questions or concerns you may have regarding your risk factors. Due to ongoing developments in ACDMPV research, the information below should not be considered current, complete or exhaustive.

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.


Introduction:

It is now well established that ACDMPV is a genetic disease, which means it occurs due to abnormalities in the genetic material in cells, the DNA. However, this does not mean that ACDMPV is familial (i.e. hereditary or inherited) in most cases. In the vast 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 being affected by ACDMPV is usually low, subject to certain caveats further described below.

Genetic Testing for ACDMPV:

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 abnormalities such as the deletion of DNA (genomic deletions) involving FOXF1 or in the areas of chromosome 16 that regulate how FOXF1 works.

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 blood samples from the child’s parents are tested and (i) if a familial link is found (i.e. a parent has a FOXF1 mutation), then the risk of recurrence is high, and (ii) if no familial link is found, then it is considered apparent de novo and the risk of recurrence is lower around 1-2% (due to gonadal and somatic mosaicism or an unknown gene, see further details below).

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

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

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

Step 3:  Whole exome or genome testing if no mutation or deletion found above. This involves testing all genes in a person’s DNA.


How do the genetics of ACDMPV work?

The genetic bases 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 genetic abnormality discussed above (i.e. a mutation or genomic deletion). The genetic abnormalities responsible for ACDMPV in the remaining 10-20% of cases are currently being investigated, including whole exome and whole genome sequencing analyses.

In approximately 90% of cases of ACDMPV where a genetic abnormality has been found in the child, it appears to have arisen de novo (spontaneously) and is NOT inherited from a parent. This means that the abnormality arose as a new spontaneous genetic abnormality in the affected child without it being passed on from a parent. However, please keep in mind these additional caveats even if it is considered an apparent de novo case:

1. Gonadal mosaicism: In rare cases a genetic abnormality is found in the child with ACDMPV and not the parents but the family have a further child with ACDMPV. Baylor believes this rare circumstance could be caused by the presence of a gonadal mosaicism. This means that there is a mixture of eggs in the mother’s ovary, some of which are normal, and some of which have a genetic abnormality associated with ACDMPV.  This abnormality is limited to the eggs and not present in the mother’s blood or in the father’s sperm. 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: This is when a person has different populations of cells in their body that have different versions of a gene (e.g. both normal and abnormal copies of a gene). This arises due to mutations as the cells in our body divide. Normal genetic tests often fail to find low-levels of somatic mosaicism (<10-20% of DNA) as it is extremely difficult to detect. Baylor routinely tests for low-level somatic mosaicism in parents of ACDMPV infants with FOXF1 related deletions, but not FOXF1 mutations. This is because the test has been unreliable at detecting mutations at such levels. However, Baylor is working on a more sensitive method for mutation testing (approaching PCR sensitivity) and this has been performed on some recent families.  Note Baylor intends to continue to conduct testing for somatic mosaicism related to FOXF1 related deletions but such testing may not regularly be available for somatic mosaicism related to FOXF1 mutations. Note also the risk of somatic mosaicism presenting in various types of tissues is not specific to ACDMPV and is a general concept for many types of diseases and such risks should be professionally addressed in any genetic counseling or decision making process.

3.  Unknown Gene: 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 or genome 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.

How to take samples from a child for genetic testing:

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). A blood sample for genetic testing can be collected either before or after an infant is placed on ECMO. This is because the donor blood that is used for ECMO has the white blood cells that are used in genetic testing removed before use.

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.

Key takeaway:

Overall the risk of having more than one child affected by ACDMPV is somewhere around 10% before the results of parental blood test are known (due to familial ACDMPV and gonadal and somatic mosaicism). 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 gonadal and apparent somatic mosaicism or an unknown gene).


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.