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

Abstract

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.

Fig. 1

Pedigrees of 10 families with FG syndrome (see Figures, Supplemental Digital Content 1 and 2, http://links.lww.com/GIM/A87 and http://links.lww.com/GIM/A88.). Family 1 has not been reported previously. Family 2, III-1 was included in the report of Briault et al. Family 3, IV-1 was reported by Lyons et al. Family 4, III-2, III-4, III-5, III-9, and III-10 (the original FG family) were reported first by Opitz and Kaveggia. Family 4, III-11 was first reported by Riccardi et al. as patient I-6. Family 5, II-1, II-3, and II-10 were reported by Keller et al. Family 6, III-3 was reported by McCardle and Wilson as J.B. Family 7 was reported by Graham et al. as Family 1. Family 8 was reported by Graham et al. as Family 3. Family 9 was reported by Graham et al. and by Opitz et al. as Family 3, Patient 4. Family 10 was reported by Graham et al.

Fig. 2

a–d, Family 1, Patient IV-2, at age 2 years 3 months, 11 years 10 months, and 18 years.