the weird genetics of cf, R117H/7T 'n stuff

[Guest guest]

Hi,

JOAN, Meagan has deltaF508, R117H, 9T, 7T. What the heck are 9T and 7T,

you ask? Good question. The " T-variants " are, as far as I can see,

genetically incomprehensible to mere mortals-- I've posted pretty good

descriptions of what they are on Cystic-L in the past (quoting heavily from

those well versed in genetics) when I was on that list, so you can plow

through the archives if you're interested. For practical purposes, when an

individual has R117H and another mutation (or when they're homozygous for

R117H), 5T can make the disease more severe, and 7T produces individuals who

tend to be pancreatic sufficient, have mild pulmonary disease with late

onset (often in adolesence or even adulthood), and have pretty normal life

expectancies. Many people with R117H aren't diagnosed until they're adults.

(A note on 5T-- it's such a nasty little variant, that there've been cases

of CF recorded in individuals with DeltaF508 and 5T, even though 5T isn't

considered a CF mutation.)

Here's the REALLY weird thing; some individuals who have R117H for one of

their mutations and also have 7T can be completely a-symptomatic! This is

part of why it was really hard to get a dx for Meagan even though we knew

her gene type way back in January. Like many people with R117H, Meagan had

normal sweat tests (25 at 3 weeks, and 37 at 4 yrs. old). So because she

had R117H, 7T, and normal sweat chloride levels, our pulm thought she might

fall into the a-symptomatic cattegory and just have really nasty asthma.

Thus the Nasal Potential Difference test, which showed a textbook CF-type

response (high nasal voltage and no response to the various medications they

drip into the nose during the test). So once Meagan had her positive NPD,

our pulm. talked to a doctor at s Hopkins that's done a lot of research

on R117H and the T-variants as they relate to phenotype, and he's the one

who spelled out what to expect, based on the patients at s Hopkins and

U.N.C. with Meagan's genotype that they've been studying for a number of

years. The one thing he couldn't offer any insight into was when Meagan

will begin to exhibit more typical pulmonary disease, though it will

probably be later than with most other mutations.

There's also been some research in Europe by Dr. B. Tummler (Germany) on

mild/atypical forms of CF (including, you guessed it, R117H). In his speech

to the '95 Europaen CF conference, Tummler referd to a child who was

homozygous for E92K whose only symptoms were salt loss and dehydration when

exposed to heat, and he thinks that mutation primarily affects salt

absorbtion in the sweat ducts. There are also two mutations (one of which

is R117H) in which males may have no other symptoms than congenital absence

of vas deferens. With tools such as NPD testing, they're discovering that

CF presents a much broader range of phenotypes than previously suspected,

and there's currently a lot of controversy about what fits the diagnosis of

CF and what doesn't-- just having two mutations doesn't mean an automatic

diagnosis with some mutations.

So, they're starting to do more research on phenotype/genotype correlation,

and there are a handful of " mild " forms they've discovered, but my

impression is that there is a lot left to discover in this area. I did a

lot of research on what's been written on all of this when Meagan was

getting diagnosed, and it's really interesting. How's that for a LONG

answer to your question as to why I refer to Meagan as having " mild " CF?

Just one of those things that's so complicated it's hard to sum up in a

paragraph or two :-)

, mom of Meagan 4 (cf, asthma) & Kailin 6 (asthma)