Two male sibs with severe micrognathia and a missense variant in MED12.
Missense variants in MED12 cause three partially overlapping dysmorphic X-linked intellectual disability (XLID) syndromes: Lujan-Fryns syndrome (also known as Lujan syndrome), FG syndrome (also known as Opitz-Kaveggia syndrome) and X-linked Ohdo syndrome. We report a family with two severely micrognathic male sibs, a 10½ year old boy and a fetus, in which hemizygosity for a previously unreported missense variant in exon 13 of MED12 (NM_005120.2), c.1862G > A, p.(Arg621Gln) was detected by whole exome sequencing. The affected sibs shared no other rare variant with relevance to the phenotype. X-chromosome inactivation in blood was completely skewed (100:0) in the unaffected heterozygous mother, most likely as a result of preferential inactivation of the X-chromosome harbouring the missense variant in MED12. Neither the unaffected brother nor the unaffected maternal grandfather carried the missense variant in MED12. In the 10½ year old boy, upper airway obstruction secondary to Pierre Robin sequence necessitated a tracheostomy for the first 10 months of life. He has mild to moderate intellectual disability and some dysmorphic features seen in MED12-related syndromes. In addition, he has a horizontal gaze paresis, anomalies of the inner ear, and a cervical block vertebra. This report contributes to the expanding phenotypic range associated with MED12-mutations.
Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway. Electronic address: prescott@online.no.
Trine E
TE
Prescott
Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
Mari Ann
MA
Kulseth
Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
Ketil R
KR
Heimdal
Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
Barbro
B
Stadheim
Department of Radiology and Nuclear Medicine, Oslo University Hospital, 0424, Oslo, Norway.
Einar
E
Hopp
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
Tomasz
T
Gambin
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Zeynep H
ZH
Coban Akdemir
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Human Genome Sequencing Center (HGSC), Baylor College of Medicine, Houston, TX, 77030, USA.
Shalini N
SN
Jhangiani
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Human Genome Sequencing Center (HGSC), Baylor College of Medicine, Houston, TX, 77030, USA.
Donna M
DM
Muzny
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Human Genome Sequencing Center (HGSC), Baylor College of Medicine, Houston, TX, 77030, USA.
Richard A
RA
Gibbs
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Human Genome Sequencing Center (HGSC), Baylor College of Medicine, Houston, TX, 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA; Texas Children's Hospital, Houston, TX, 77030, USA.
James R
JR
Lupski
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Norwegian National Unit for Newborn Screening, Oslo University Hospital, 0424, Oslo, Norway.
Asbjørg
A
Stray-Pedersen
D005091:Exons; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D008844:Micrognathism / Q000175:diagnosis* / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D035781:Siblings; D014057:Tomography, X-Ray Computed; D049951:X Chromosome Inactivation
C460107:MED12 protein, human; D056892:Mediator Complex
Intellectual disability; MED12; Mental retardation; Micrognathia; X-linked