Lujan Syndrome, FG Syndrome Type 1 and Ohdo Syndrome via the MED12 Gene

Lujan Syndrome (LS; also known as Lujan-Fryns Syndrome) and FG Syndrome Type 1 (FGS1; also known as Opitz-Kaveggia Syndrome) are allelic disorders with overlapping clinical phenotypes. LS and FGS1 share the clinical findings of cognitive impairment and hypotonia (Lyons et al. J Med Genet 46:9-13, 2009). However, LS is further characterized by a Marfan-like appearance, which include a marfanoid habitus (large head; tall, thin body habitus) and craniofacial changes (long, thin face; high nasal root; high, narrow palate; and short philtrum) (Lujan. Am J Med Genet 17:311-322, 1984; Schwartz et al. J Med Genet 44:472-477, 2007). Conversely, FGS1 is further characterized by constipation, anal anomalies, small and simple ears, tall and prominent forehead, downslanting palpebral fissures, broad thumbs and halluces, and abnormalities of the corpus callosum (Opitz et al. Z Kinderheilkd. 117:1-18, 1974; Risheg et al. Nat Genet 39:451-453, 2007). LS has overlapping clinical features with Loeys-Dietz syndrome (LDS, OMIM 609192; 608967; 610380; 610168), Shprintzen-Goldberg syndrome (OMIM# 182212), Fragile X syndrome (OMIM 300624) and Snyder-Robinson syndrome (OMIM 309583). FGS1 has overlapping clinical features with alpha-thalasemia X-linked mental retardation syndrome (ATRX; OMIM 301040), Coffin-Lowry syndrome (OMIM 303600), Rubinstein-Taybi syndrome (OMIM 180849) and Fragile X syndrome (OMIM 300624). Maat-Kievit-Brunner (MKB) type Ohdo syndrome is characterized by intellectual disability and distinctive facial features, which include blepharophimosis, ptosis, a long philtrum and a narrow mouth. The facial features become more pronounced and the face becomes more triangular as the individual ages (Maat-Kievit et al. Am J Med Genet 47:901-906, 1993).

LS, FGS1 and Ohdo syndrome, MKB type are inherited in an X-linked recessive manner. LS syndrome is caused by a c.3020A>G (p.Asn1007Ser) mutation in exon 22 of the MED12 gene (Schwartz et al. J Med Genet 44:472-477, 2007). FG syndrome is caused by a c.2881C>T (p.Arg961Trp) mutation or a c.2873G>A (p.Gly958Glu) mutation in exon 21 of MED12 (Risheg et al Nat Genet 39:451-453, 2007; Rump et al. Clin Genet 79:183-188, 2011). Three different missense mutations in MED12 have been found in individuals with Ohdo syndrome, MKB type (Vulto-van Silfhout et al. Am J Med Genet 92:401-406, 2013). MED12 encodes for the mediator of RNA polymerase II transcription subunit 12, which serves as an interface between transcription factors and RNA polymerase II. The mediator complex comprises 25 subunits organized into four modules. The MED12 protein is part of the module needed for repression of transcription (Zhou et al. Mol Cell Biol 26:8667-8682, 2006; Philibert and Madan. Pharmacogenomics 8:909-916, 2007).

The prevalence of FGS, LS and Ohdo syndrome, MKB type is unknown. MED12 mutations have been identified in approximately 13% of individuals clinically diagnosed with FGS (Risheg et al. Nat Genet 39(4): 451-453, 2007).

Deletion/duplication mutations in MED12 are not known to cause Lujan, FG or Ohdo syndrome, MKB type. No gross deletions/duplications have been reported in MED12 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the MED12 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.