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

Division of Medical Genetics, Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA 92354, USA.
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 7.33). 11/2009; 11(11):769-75. DOI: 10.1097/GIM.0b013e3181bd3d90
Source: PubMed


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% specificity. 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.

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Available from: John M Graham, Apr 13, 2015
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    • "They may benefit from mood stabilizers, and their transition to a community living situation can be challenging without careful planning and timely behavioral intervention. Currently, 10 families with FG syndrome and the recurrent p. R961W mutation in MED12 have been reported (including a total of 23 affected males), and diagnostic criteria have been proposed [Clark et al., 2009]. A family history of X-linked mental retardation, deceased male infants and/or multiple fetal losses was documented in all families. "
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    ABSTRACT: 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 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 three 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. © 2013 Wiley Periodicals, Inc.
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