Lujan–Fryns syndrome

Lujan-Fryns syndrome is caused by germline pathogenic variants in MED12 (Xq13.1). The recurrent missense variant p.Asn1007Ser has been reported in three families with classical Lujan syndrome. MED12 encodes a subunit of the Mediator complex, which acts as an interface between transcription factors and RNA polymerase II and contributes to transcriptional regulation through the Wnt, sonic hedgehog, REST, and SOX9 pathways. Missense variants in the LS domain disrupting MED12 function impair this regulatory activity.

Lujan-Fryns syndrome is inherited in an X-linked recessive manner. Males with a MED12-related disorder are not known to reproduce. Female heterozygotes are typically unaffected and have a 50% risk of transmitting the variant to each child. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Lujan-Fryns syndrome is diagnosed primarily by molecular genetic testing. The diagnosis is established in a male proband by identification of a hemizygous pathogenic variant in MED12 and in a female with suggestive findings and a heterozygous pathogenic variant in MED12. However, female carriers are mostly unaffected.

Main differential diagnoses include:

• : marfanoid habitus with craniosynostosis and intellectual disability; autosomal dominant; SKI
• : marfanoid habitus with ectopia lentis and aortic root dilatation, without intellectual disability; autosomal dominant; FBN1
• Homocystinuria: marfanoid habitus with ectopia lentis, intellectual disability, and thromboembolism; elevated plasma homocysteine; autosomal recessive; CBS

• Establishing the diagnosis: molecular genetic testing confirms the clinical suspicion and provides a definitive diagnosis at the molecular level.
• Specific and individualised surveillance: knowledge of the underlying pathogenic variant supports tailored monitoring of growth, development, behaviour, neurological, ophthalmological, gastrointestinal, musculoskeletal, audiological and dental status, and is a prerequisite for targeted medical care, decided by the treating physicians in consultation with the affected individual.
• Family member testing: identification of the familial pathogenic variant enables predictive testing of at-risk male relatives and carrier testing of at-risk female relatives. 

• Lyons MJ. MED12-related disorders. 2008 Jun 23 [Updated 2021 Aug 12]. In: Adam MP, Bick S, Mirzaa GM, et al., editors.. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301719.
• Schwartz CE, Tarpey PS, Lubs HA, Verloes A, May MM, Risheg H, et al. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet. 2007;44(7):472-7. doi:10.1136/jmg.2006.048637. PMID:; PMCID: PMC2597996.
• Srivastava S, Niranjan T, May MM, Tarpey P, Allen W, Hackett A, et al. Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders. Mol Genet Genomic Med. 2019;7(4). doi:10.1002/mgg3.569. PMID:; PMCID: PMC6465656.