Work has begun on a research project to find FGS3 through exome sequencing after the FGSFA offered Drs. Opitz and Jorde the funding to do so at the University of Utah. It is only through the careful use of FGSFA funds and the generosity of our families who have made donations and given time to fundraising projects over the years that we are able to offer the funding necessary for this research. Heartfelt thanks to all who have contributed of themselves in some way to the FGSFA….The FGSFA Board of Directors

Email from Dr. Opitz, dated Feb. 8, 2011:

The new methodology of exome sequencing has been a dramatic advance in medical genetics allowing researchers to discover causative genes in conditions previously considered genetically intractable. This is especially true of sporadic syndromes, i.e. syndromes where each case was a single isolated occurrence in the family. A famous recent example is the “kabuki” syndrome, always sporadic, where exome sequencing, i.e. sequencing only the exons – open reading frames – not the whole gene, exons and introns, of the entire genome readily and reliably yielded the causative gene. The method was applied to the conditions of Dr. Lynne Jorde’s two wonderful step children with a post-axial acrofacial dysostosis and a ciliary disorder which finally identified both mutant genes, both recessive. Their mother, Debbie Jorde, has written a fascinating account of the story (Eight Fingers and Eight Toes) for lay persons which can serve as a useful primer for all members of the FGS Alliance.

I have had personal and highly successful experience with this method in case of a new fatal X-linked disorder where we had causative gene in hand 2, at the most 3 weeks after we autopsied the latest affected infant in this sad family from Ogden, UT with 5/probably 7 affected infants in 3 generations. But here we only had to parse the X chromosome, not all of the (autosome and sex) chromosomes. Therefore, once we have the technical kits in hand, I’m confident Dr. Jorde and his coworkers will have FGS3 in short order. I have 2 other papers in press or published with success in 2 other rare syndromes – the Perrault syndrome and the Meier-Gorlin syndrome.

So, the methodology is sound, confirmed as such world-wide, extremely effective and a fraction as expensive as only a few years ago.

The benefits for FGS3 families would be incalculable:

1) Confirming diagnosis

2) Allowing differential diagnosis with GBBB and related disorders

3) Allowing fool-proof carrier testing (vs. the useless X-inactivation approach)

4) Allowing prenatal diagnosis

5) Allow investigation of the 4 so-called Opitz paradoxes in FGS(3_:

a. Why are so many cases familial i.e. not new mutations?

b.  Why, in so many families, are more than the expected 50% of children affected, i.e. is there segregation distortion in FGS3?

c.   Why, even in some familial cases, are girls more severely affected than boys?

d.   And if the mutation rate is found to be low, is there a selective advantage to having the gene?

All the best to all of you!

Faithfully,
John