why I think CHARGE is genetic

[Guest guest]

,

I would be happy to go over this again. It is worth reviewing every now

and then for new people on the list and as a review for those who have

heard it again. You asked why I think CHARGE is genetic. There is a lot

of evidence, which keeps on accumulating:

1) Children with CHARGE look as much like one another as do children

with other genetic conditions, such as Down syndrome or VCF. The fact

that they have so many features in common (including how they move -

they look alike from a block away) make me think they all have the same

thing. Children that have a non-genetic condition such as VATER

association may have lots of similarities on paper (similar medical

problems), but they look far more like their families than like one

another.

2) The incidence of CHARGE is about 1 in 10,000 to 12,000 births, but

the recurrence risk is 1-2%. This is typical of new mutations to

dominant genetic conditions (such as Marfan syndrome, neurofibromatosis

or achondroplasia). The 1-2% recurrence risk (rather than 1 in 10,000

again) is due to the new genetic mutation happening in the tissue that

makes sperm or eggs - not just in the single sperm or egg that formed

the first affected child.

A mutation is a change in the genetic material (everything has to start

somewhere). A dominant condition is one that, once a person has it,

there is a 50-50 chance of passing the gene to the next generation,

which leads to the next observation:

3) We have evidence of parents with CHARGE having children with CHARGE,

with about 50% rate of recurrence - actually it almost looks higher

(e.g. both kids affected), but that may be by chance in the small number

of families we know. I know one family with 6 affected individuals in 3

generations. There are unaffected individuals in that family, too. The

unaffected individuals did not have children with CHARGE. In these

families, there is no question CHARGE is genetic - and I am convinced

they have the same condition as other famous - the spectrum of features

and " look " is identical. Several features now thought to be typical of

CHARGE we first published in 1985 as features of the 3 generation

family.

4) There is documented evidence of advanced paternal age. That is, on

average, fathers of children with CHARGE are older than fathers of

children with random birth defects (e.g. isolated cleft lip). Most

people have heard that Down syndrome (which is caused by an extra

chromosome) happens more often in children of older mothers. In the

genetics community, we know that new dominant mutations are more likely

to occur in children of older fathers.

5) CHARGE looks so much like VCF (22q deletion syndrome) - which is a

tiny deletion of chromosome 22. A child with VCF can be either

represent a new mutation or be inherited from a parent like a dominant

gene. Both CHARGE and VCF affect lots of organ systems and are extremely

variable, even within families. There is a test for VCF (FISH for

del22q), which we recommend in kids with CHARGE because the medical

problems overlap so much.

To me, all of this evidence is staggering. I am absolutely convinced

CHARGE is genetic in origin. We will find the gene or microdeletion

eventually.

That said, I do not have a good explanation for why there is such

variablity or every feature of CHARGE. The longer I am in the field of

genetics, the less I feel like I know - things just aren't as simple as

we once thought. It will take a long time to make sense of

variability. Things that may well make a difference from one child with

CHARGE to another include:

1) the 30,000 other genes everybody has - some will make things better,

some worse. No condition exists in a genetic vacuum.

2) there may be different versions of/variations on the CHARGE gene (for

most genetic conditions, there are many different mutations - point

mutations, deletions, duplications - within a gene which can cause the

gene to malfunction and cause the syndrome, with slightly different

features),

3) There are undoubtedly environmental factors involved. The obvious

things to think about are maternal exposures during pregnancy (which

could theoretically make a heart defect worse, or something like that).

But we may discover that preconceptual exposures (maternal or paternal)

have an an effect as well.

4) We know very little about what it does to have anesthesia a zillion

times or be fed by IV for weeks or months.... postnatal things obviously

won't affect which birth defects a child has, but may turn to make a

difference in behavior or learning abilities. Food allergies,

medication allergies, reactions to things. The reactions are are

probably pre-programmed in the genes, but we don't know what effect the

reactions themselves have.

That's probably more than you wanted to know. And I didn't even talk

about the fact that we don't know what the mild end of the spectrum is.

Once we find the gene, we will be able to test other family members and

see if anyone carries a " hidden " form of the gene. Ok, I'm done for

today.

Meg

Meg Hefner, MS

Genetic Counselor

St. Louis MO

meg@...