June 2015

A (brief) glossary of genetics

• DNA: a molecule that carries the genetic instruction used in the development and function of all living organisms. DNA is expressed by the production of proteins that carry out the genetic instructions. Genes carry the codes for these proteins. The expression of genes is controlled (regulated) by areas of DNA close to the genes.
• Familial: A disease that runs in a family as one or both parents carry a genetic abnormality and can thus pass it on to multiple offspring (also referred to as hereditary or inherited).
• Chromosome: A DNA structure found in cells containing many genes. Humans have 23 pairs of chromosomes.
• De Novo (or sporadic): The opposite of familial. A genetic abnormality that occurs for the first time in an individual and is NOT present in the parents of the affected individual.
• Mutation: A change in the DNA sequence of a gene. This results in a change to the protein that the gene is responsible for producing. These are usually small changes, e.g. a switch from one DNA unit to another
• Deletion: The removal of a piece of genetic material. This can be a single DNA unit or a larger section of a chromosome.
• Paternal imprinting: The inactivation of a copy of a gene inherited from the father of an infant so that the gene is silent and not expressed. This leaves only the gene copy inherited from the infant’s mother active and expressed.
• Gonadal Mosaicism: This occurs when a person (in this case the mother of an infant with ACDMPV) has two or more populations of cells in her ovary. One population of cells contains normal genetic material while the others contain genetic abnormalities. The genetic abnormality is confined to cells in the ovary, however, and is not present in the DNA from the mother’s other tissues. If two eggs with the genetic abnormality were released and fertilized, then both children would have ACDMPV even though a sample of the mother’s blood would not show a genetic abnormality.

A summary of the genetics of ACDMPV

It is now well established that ACDMPV is a genetic disease. This means that ACDMPV occurs due to abnormalities in the DNA. Humans carry DNA in all of our cells that make us up and it acts as the blueprint to make us who we are. However, this doesn’t mean that ACDMPV is familial in most cases. In almost all cases the genetic abnormalities (mutations and deletions) that are found in infants with ACDMPV are not present in either of their parents and thus the risk of other children being affected by ACDMPV is low.

The genetics of ACDMPV are complex and require the use of some genetic terms. Please see the glossary above for an explanation of some of these.

Two broad types of genetic abnormality 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 areas of chromosome 16 that regulate the expression of the FOXF1 gene. 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 these abnormalities. 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.

Based on the cases described so far, the FOXF1 gene seems to be subject to paternal imprinting. The FOXF1 gene that an infant inherits from his/her father is inactive and not expressed, thus all cases of ACDMPV arise by the genetic abnormalities arising on the chromosome inherited from an infant’s mother. In approximately 90% of cases of ACDMPV where a genetic abnormality has been found it appears to have arisen de novo and is not familial. The abnormality arises in the mother’s ovary early in her life, often before she was born.

Four families with more than one child affected by ACDMPV have been described in research conducted at the Baylor College of Medicine so far. There might not be a family history of ACDMPV as a result of paternal imprinting. This means that the genetic abnormality only results in ACDMPV when it is inherited from an infant’s mother. In three of these families, there was a mutation in FOXF1 found in the mother’s blood sample. One case of ACDMPV due to gonadal mosaicism has been described.

This means that overall, considering familial ACDMPV and gonadal mosaicism, the risk of having more than one child affected by ACDMPV is around 10%. The risk of having more than one infant with ACDMPV if neither parent carries the genetic abnormality is 1-2% (due to gondadal mosaicism).

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 tissue, for example a lung biopsy or autopsy (post mortem). It is important to test such material for the following:

1. FOXF1 gene sequencing to detect a mutation in FOXF1. This test is performed in Baylor College of Medicine, in Houston, Texas, USA by Professor Stankiewicz’s laboratory. Some other centres are now able to do this test (for example Great Ormond Street Hospital, London, UK);

2. Other genetic abnormalities such as deletions in chromosome 16 close to the FOXF1. This can be done using a widely-available genetic test called array CGH (Comparative Genomic Hybridisation).

If an infant 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 and amniocentesis. This test is offered by the clinical diagnostic laboratories at Baylor College of Medicine.

A blood sample for genetic testing can be collected 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.