Dr. John Opitz – Together We Can Make A World of Difference

FG Syndrome Family Alliance

Together We Can Make A World of Difference

The following is an excerpt from an email received in March, 2010, from Dr. John Opitz, Professor of Pediatrics, Human Genetics and Obstetrics and Gynecology, at the University of Utah:

I’ll be done teaching at the end of April and as of 4/28 will be back in clinic every Wednesday morning between 8:00-10:00 (at 10:00 the latest I must be in Pathology – if we have an autopsy that day – I also function as genetic coordinator for the stillbirth program). Thus, every Wed AM I can see 2 new FGS families.

My contact information remains unchanged (john.opitz@hsc.utah.edu) and I hope will still unchanged until I retire in 4-5 years (BD 8/15/1935).

You will, of course, be the first to hear of any new developments in the genetics of FGS. We just now sent DNA on the prototype Family 1 from Utah, that mapped the locus for FGS3, to a group of collaborators at Ohio State University in Columbus. As you know, FGS3 maps to Xp22.22. That is also the location of the gene MID1 implicated in the cause of the GBBB (“Opitz”) syndrome which shares many developmental similarities with FGS3.

Over 2 years ago a senior postdoctoral fellow at Columbus introduced me to a wonderful little boy with a tiny (but real) deletion (loss) of DNA from MID1 “who did not have Opitz/GBBB syndrome.” When mom and the boy came to SLC last summer for consultation he had evident FGS, thus FGS3. Therefore, we have a potentially extremely valuable lead to test the hypothesis that FGS3 is due to mutations of MID1, rather less severe ones than seen in the GBBB children, hence of lesser clinical severity.

So, the gene defects of FGS1, FGS2, FGS4, FGS5, FGS6 and –7 are known; only FGS3 remains elusive. FGS1 is a rare true mental retardation syndrome (only 7 out of 700 families are known to me).

What remains unknown in FGS2 is how many children/boys with a FLNA mutation have periventricular nodular heterotopia (PVNH), on MRI, and conversely, how many with PVNH have an FLNA mutation.

We can probably forget about FGS4 and FGS5, seen respectively only once in an Italian family and in a Brazilian family. I’m not sure I’ve ever made the diagnosis of FGS6 or -7 securely; one should think of FGS6 whenever one sees a relative in a family with a big head, speech delay, and a Lujan-Fryns like phenotype (true also of FGS1). Thus, I am inclined to postulate at the moment that FGS3 will ultimately turn out to be the most common form of FGS.

A final note. Nowadays, before diagnosis of FGS is “set in concrete,” at least one affected boy in each family must have a micro-array (uCG) study to be sure the child does not have one of many conditions mimicking FGS due to a microdeletion or microduplication detectable on uCGH. Thus, all individuals previously diagnosed as “Dubowitz syndrome” and then rediagnosed as having FGS with small head (frequently with metopic and/or other craniosynostosis) should have a uCGH study to rule out the 1q21.1 microdeletion syndrome.

FGS Type/Gene Location/Reference:
1 and Lujan-Fryns MED12 Xq21-Xq22 Risheg et al., Nat Genet 39(4): 451-3, 2007
2 (PVNH) FLNA Xq28 Hehr et al., J Med Genet 43(6): 541-4, 2006; Unger et al., Am J Med Genet 143A: 1876-9, 2007
3 MID1 ? Xp22.22 Dessay et al., ibid 112:6-11, 2002
4 CASK Xp11 Piluso et al., Am J Hum Genet, outline 2/5/2009
5 ? 4 mB duplication Xq22.3 Jehee et al., Am J Med Genet 139: 221-226, 2005
6 and Lujan-Fryns UPF3B Xq25-q26 Tarpee et al., Nat Genet 39(9): 1127-1133, 2007
7 BRWD3 Xq21.1 Field et al., Am J Hum Genet. 81: 367-374, 2007

The best way to become acquainted with a subject is to write a book about it – Benjamin Disraeli