NORD gratefully acknowledges Michael J. Lyons, MD, Associate Clinical Geneticist, Greenwood Genetic Center, for assistance in the preparation of this report.
FG syndrome type 1 (FGS1) is an X-linked genetic disorder that is characterized by poor muscle tone (hypotonia), intellectual disability, constipation and or anal anomalies and complete or partial absence of the part of the brain that connects the two hemispheres of the brain (corpus callosum). Other features of the disorder are small and simple ears, tall and prominent forehead, wide and flat thumbs and great toes and downslanting eyes. Additional features may include a large head (macrocephaly), widely spaced eyes (ocular hypertelorism) and upswept frontal hair. Seizures and congenital heart defects have also been reported.
Individuals with FGS1 often have characteristic behaviors that can include hyperactivity, friendliness and attention seeking.
FGS1 is typically caused by a recurrent abnormality (mutation) in the MED12 gene on the X chromosome located at Xq13. The MED12 gene is responsible for production of the MED12 (TRAP230) protein that is involved in the regulation of transcription.
FGS1 is an X-linked genetic disorder. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
The prevalence of FGS1 is unknown. The spectrum of disorders caused by mutations in this gene is still being defined. Some individuals previously diagnosed with FG syndrome do not have a MED12 gene mutation and, therefore, probably have a different reason for intellectual disability.
FGS1 syndrome is suspected based on the presence of physical characteristics. Molecular genetic testing for the MED12 gene is available and is the only way to confirm the diagnosis.
The symptoms of FGS1 syndrome are treated individually. This usually involves care by a team of providers including a pediatrician, neurologist, cardiologist, surgeon, gastroenterologist and psychologist. Early intervention with physical, occupational and speech therapy should be initiated as soon as possible.
Genetic counseling is recommended for affected individuals and their family members.
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Graham JM Jr. FG Syndrome In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:193-4.
Narayanan DL, Phadke SR. A novel variant in MED12 gene: Further delineation of phenotype. Am J Med Genet A. 2017 Aug;173(8):2257-60.
Prontera P, Ottaviani V, Rogaia D, et al. A novel MED12 mutation: Evidence for a fourth phenotype. Am J Med Genet A. 2016 Sep;170(9):2377-82.
Isidor B, Lefebvre T, Le Vaillant C, et al. Blepharophimosis, short humeri, developmental delay and Hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations. Am J Med Genet A 2014 164A:1821-5.
Lesca G, Moizard MP, Bussy G, et al. Clinical and neurocognitive characterization of a family with a novel MED12 gene frameshift mutation. Am J Med Genet A. 2013 Dec;161A(12):3063-71.
Vulto-van Silfhout AT, de Vries BB, van Bon BW, et al. Mutations in MED12 cause X-linked Ohdo syndrome. Am J Hum Genet. 2013 92:401-6.
Graham JM Jr, Schwartz CE. MED12 related disorders. Am J Med Genet A. 2013 Nov;161A(11):2734-40.
Rump P, Niessen RC, Verbruggen KT, et al. A novel mutation in MED12 causes FG syndrome (Opitz-Kaveggia syndrome). Clin Genet. 2011 Feb;79(2):183-8.
Clark RD, Graham JM Jr, et al. FG syndrome, an X-linked multiple congenital anomaly syndrome: The clinical phenotype and an algorithm for diagnostic testing. Genet Med. 2009 Nov;11(11):769-77.
Risheg H, Graham JM, Clark RD, et al. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet 2007;39:451-3.
Schwartz CE, Tarpay PS, Lubs HA, et al. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet A 2007;44:472-7.
Battaglia A, Chines C and Carey JC. The FG syndrome:Report of a large Italian series. Am J Med Genet 2006;140A:2075-9.
Jehee, FS, Rosenberg C, Krepischi-Santos, AC, et al. An Xq22.3 duplication detected by comparative genomic hybridization microarray (Array-CGH) defines in a new locus (FGS5) for FG syndrome. Am J Med Genet 2005;139A:221-6.
Piluso G, Carella M, D’Avanzo M, et al. Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family. Hum Genet 2003;112(2):124-30.
Ozonoff S, Williams BJ, Rauch AM, et al. Behavioral phenotype of FG syndrome: cognition, personality and behavior in eleven boys. Am J Med Genet 2000;97:112-118.
Meroni G, Cainarca S, Berti C, et al. Identification and characterization of proteins that interact with midin, the Opitz syndrome gene product. Am Soc Hum Genet Program and Abstract 2000;abstract 959: p. 183.
Graham JM Jr, Superneau D, Rogers RC, et al. Clinical and behavioral characteristics in FG syndrome. Am J Med Genet 1999;85:470-475.
Opitz JM, Richieri-da Costa A, Aase JM, et al. FG syndrome update 1998: note of 5 new patients and bibliography. Am J Med Genet 1998;30:309-328.
Graham JM Jr, Tackels, D, Dibbern K, et al. FG syndrome: report of three new families with linkage to Xq12-q21.1 Am J Med Genet 1998;80:145-156.Briault S, Hill R, Shrimpton A, et al. A gene for FG syndrome maps in the Xq12-X21.31 region. Am J Med Genet 1997;73:87-90.
Briault S, Hill R, Shrimpton A, et al. A gene for FG syndrome maps in the Xq12-X21.31 region. Am J Med Genet 1997;73:87-90.
Kato R, Niikawa N, Nagai T, et al. Japanese kindred with FG syndrome [letter]. Am J Med Genet 1994;52:242-243.
Lyons MJ. MED12-Related Disorders. 2008 Jun 23 [Updated 2016 Aug 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1676/ Accessed March 8, 2018.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 305450; Last Update 03/21/2012. http://omim.org/entry/305450 Accessed March 8, 2018.
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