Language and development in FG syndrome with callosal agenesis

American J of Med Genetics Pt A

Schwartz

2013

MED12 is a member of the large Mediator complex, which has a critical and central role in RNA polymerase II transcription. As a multiprotien complex, Mediator regulates signals involved in cell growth, development and differentiation, and it is involved in a protein network required for extraneuronal gene silencing and also functions as a direct suppressor of Gli3-dependent Sonic hedgehog signaling. This may may explain its role in several different X-linked intellectual disability syndromes that share some overlapping clinical features. This review will compare and contrast four different clinical conditions that have been associated with different mutations in MED12, which is located at Xq13. To date, these conditions include Opitz–Kaveggia (FG) syndrome, Lujan syndrome, Ohdo syndrome (Maat-Kievit-Brunner type, or OSMKB), and one large family with profound X-linked intellectual disability due to a novel c.5898insC frameshift mutation that unlike the other 3 syndromes, resulted in affected female carriers and truncation of the MED12 protein. It is likely that more MED12 mutations will be detected in sporadic patients and X-linked families with intellectual disability and dysmorphic features as exome sequencing becomes more commonly utilized, and this overview of MED12-related disorders may help to correlate MED12 genotypes with clinical findings.

Section: Opitz-kaveggia (Fg) Syndromementioning

confidence: 70%

MED12 related disorders

American J of Med Genetics Pt A

Schwartz

2013

“…1 Family 4, III-11 was first reported by Riccardi et al 5 as patient I-6. Family 5, II-1, II-3, and II-10 were reported by Keller et al 4 Family 6, III-3 was reported by McCardle and Wilson 6 as J.B. Family 7 was reported by Graham et al 8 as Family 1. Family 8 was reported by Graham et al 8 as Family 3.…”

Section: Figmentioning

confidence: 89%

“…In 1993, McCardle and Wilson 6 reported FG syndrome in their patient, J.B. (designated here as III-3 in Family 6). The maternal uncle of the proband, II-4, was born in 1965 and died at 10 months of age.…”

Section: Patient Summariesmentioning

confidence: 99%

FG syndrome, an X-linked multiple congenital anomaly syndrome: The clinical phenotype and an algorithm for diagnostic testing

Clark

Friez

et al. 2009

Genetics in Medicine

FG syndrome is a rare X-linked multiple congenital anomaly-cognitive impairment disorder caused by the p.R961W mutation in the MED12 gene. We identified all known patients with this mutation to delineate their clinical phenotype and devise a clinical algorithm to facilitate molecular diagnosis. We ascertained 23 males with the p.R961W mutation in MED12 from 9 previously reported FG syndrome families and 1 new family. Six patients are reviewed in detail. These 23 patients were compared with 48 MED12 mutation-negative patients, who had the clinical diagnosis of FG syndrome. Traits that best discriminated between these two groups were chosen to develop an algorithm with high sensitivity and specificity for the p.R961W MED12 mutation. FG syndrome has a recognizable dysmorphic phenotype with a high incidence of congenital anomalies. A family history of X-linked mental retardation, deceased male infants, and/or multiple fetal losses was documented in all families. The algorithm identifies the p.R961W MED12 mutation-positive group with 100% sensitivity and 90% spec-ificity. The clinical phenotype of FG syndrome defines a recognizable pattern of X-linked multiple congenital anomalies and cognitive impairment. This algorithm can assist the clinician in selecting the patients for testing who are most likely to have the recurrent p.R961W MED12 mutation.

“…Risheg, et al [2007] identified a recurrent p.Arg961Trp mutation in the MED12 gene in 10 individuals from 6 families with FG syndrome including a surviving affected male and his obligate carrier mother from the original report of FG syndrome (individual V-10 in Pedigree from Figure 1 in Opitz and Kaveggia 1974). We describe this surviving male’s clinical history in more detail in this report (Patient 1), as well as reporting long-term clinical histories in a male reported by McCardle and Wilson in 1993 (Patient 2), and one male from Family 1 (Patient 3) and 2 males (Patients 4 and 5) from Family 3, which were previously reported by Graham et al, [1998]. Recently, Graham et al [2008] reported two more adult males, and Clark et al, [2009] delineated the natural history of FG syndrome in additional affected males from 9 other families who all shared the p.Arg961Trp MED12 mutation.…”

Section: Introductionmentioning

confidence: 99%

Behavioral features in young adults with FG syndrome (Opitz–Kaveggia syndrome)

American J of Med Genetics Pt C

Clark

Moeschler

et al. 2010

Opitz and Kaveggia [1974] reported on a family of 5 affected males with distinctive facial appearance, mental retardation, macrocephaly, imperforate anus and hypotonia. Risheg et al. [2007] identified an identical mutation (p.R961W) in MED12 in 6 families with Opitz-Kaveggia syndrome, including a surviving affected man from the original family reported in 1974. The previously described behavior phenotype of hyperactivity, affability, and excessive talkativeness is very frequent in young boys with FG syndrome, along with socially oriented, attention-seeking behaviors. We present case studies of 5 adult males who were previously published with the clinical diagnosis of FG syndrome and then subsequently proven by Risheg et al. [2007] to have the recurrent p.R961W mutation. These individuals had episodic and longstanding behavior patterns, sometimes aggressive or self-abusing, that occurred more frequently in puberty and early adulthood. We try to describe the triggers for these behaviors, indicate how these behaviors change with advancing age, and suggest specific recommendations and interventional strategies based on the clinical histories of affected adolescent males with FG syndrome [Graham et al., 2008;Clark et al., 2009]. Young men who exhibit these behaviors may benefit from a careful examination to detect medical problems, use of mood stabilizers if needed, and/or behavioral intervention. The transition to a community living situation can be challenging without careful planning and timely behavioral intervention. They remain impulsive and can have aggressive outbursts when making the transition to adult life, but these challenges can be managed, as demonstrated by these clinical histories.