Clinical characteristics.

MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders.

Diagnosis/testing.

The diagnosis of an MED12-related disorder is established in a male by identification of a hemizygous MED12 pathogenic variant on molecular genetic testing. The diagnosis of an MED12-related disorder is established in a female with suggestive findings and a heterozygous pathogenic variant in MED12 identified by molecular genetic testing.

Management.

Treatment of manifestations: Early individualized education; physical therapy, occupational therapy, and speech therapy for developmental delays; individualized management of behavior problems; routine management of seizures, strabismus and other ocular anomalies, imperforate anus, chronic constipation, joint contractures, genitourinary anomalies, congenital heart defects, hearing loss, palate anomalies, and dental anomalies; social work support. Treatment of aneurysms, intestinal malrotation, and liver disease in females with HS as recommended by the appropriate specialist.

Surveillance: At each visit, assess growth, development, behavior concerns, neurologic issues, gastrointestinal functioning, and musculoskeletal manifestations. Annual eye examination with attention to retinal changes for individuals with HS. Annual audiology evaluation. Dental evaluation every six months, particularly for individuals with XLOS and LS. Females with HS should have an annual echocardiogram, carotid ultrasound, gastroenterology evaluation with liver function testing and consideration of clotting studies, serum bile acids, and liver ultrasound based on recommendations of a gastroenterologist; and MRA of the head and neck for aneurysms every two years.

Genetic counseling.

MED12-related disorders are inherited in an X-linked manner. If the mother of a proband is heterozygous for a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit a pathogenic variant associated with FGS1, LS, or XLOS will typically be unaffected while females who inherit a pathogenic variant associated with HS will typically be affected. Females who inherit a MED12 pathogenic variant associated with NSID will be at an increased risk of developing variable clinical features. Males with a MED12-related disorder are not known to reproduce. Once the MED12 pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing for MED12-related disorders are possible.

Suggestive Findings

An MED12-related disorder should be suspected in an individual with a phenotype associated with FG syndrome type 1, Lujan syndrome, X-linked Ohdo syndrome, or Hardikar syndrome, or with nonspecific intellectual disability with overlapping features of an MED12-related disorder.

FG syndrome type 1 (FGS1). Formal clinical diagnostic criteria for FGS1 have not been established; however, the following clinical features would be suggestive:

• Neurodevelopmental delays
• Characteristic facial features:
  • Absolute or relative macrocephaly
  • Dolichocephaly
  • Frontal hair upsweep
  • Tall forehead
  • Downslanted palpebral fissures
  • Widely spaced eyes
  • Fullness of the upper eyelids
  • Small, simple ears (≤10th percentile)
  • Open mouth
  • Long narrow face
• Broad thumbs and halluces
• Congenital anomaly (corpus callosum, anal, cardiac, skeletal)
• Hypotonia, constipation, or feeding problems
• Characteristic behavior (affable and eager to please)
• A family history consistent with X-linked inheritance

Lujan syndrome (LS). The phenotype of individuals with the recurrent MED12 pathogenic variant p.Asn1007Ser can be recognized by the presence of six of the following eight clinical features:

• Intellectual disability
• Hypotonia
• Large head (occipitofrontal circumference >75th percentile)
• Tall, thin body habitus (height >75th percentile)
• Long, thin face
• Prominent nasal bridge
• High narrow palate
• Short philtrum

Additional clinical features that can assist in recognition of individuals with LS:

• Hypernasal speech
• Dysphagia
• Micrognathia
• Long hands
• Hyperextensible digits
• Abnormalities of the corpus callosum
• Family history consistent with X-linked inheritance

X-linked Ohdo syndrome (XLOS). Diagnostic criteria have not been established for XLOS. Common clinical features include the following:

• Intellectual disability
• Blepharophimosis
• Ptosis
• Epicanthal folds
• Facial coarsening at an older age

Additional clinical features that can assist in recognition of individuals with XLOS:

• Triangular face
• Maxillary hypoplasia
• Sparse eyebrows
• Hypertelorism
• Strabismus
• Small low-set ears
• Thick alae nasi
• Wide nasal bridge
• Broad nasal tip
• Micrognathia
• Small mouth
• Dental anomalies
• Hypotonia
• Family history consistent with X-linked inheritance

Hardikar syndrome (HS). Diagnostic criteria have not been established for HS. The following clinical features have been described in association with HS:

• Cleft lip and/or cleft palate
• Biliary anomalies
• Liver disease
• Intestinal malrotation
• Pigmentary retinopathy
• Coarctation of the aorta

Additional clinical features that can assist in recognition of individuals with HS:

• Normal cognition
• Preauricular pit/tag
• Hydronephrosis
• Choledochal cyst
• Strabismus

Nonspecific intellectual disability (NSID). Individuals described with NSID due to MED12 variants have variable clinical features that often overlap but are not reported to be consistent with one of the syndromic MED12-related disorders. Clinical features commonly described in MED12-related NSID include:

• Intellectual disability
• Behavior issues
• Feeding problems
• Growth delays
• Abnormalities of the corpus callosum
• Hypotonia
• Blepharophimosis
• Low-set, posteriorly rotated ears
• Prominent forehead
• Palatal anomalies
• Constipation

Establishing the Diagnosis

Male proband. The diagnosis of an MED12-related disorder is established in a male proband by identification of a hemizygous pathogenic (or likely pathogenic) variant in MED12 by molecular genetic testing (see Table 1).

Female proband. The diagnosis of an MED12-related disorder is usually established in a female proband with suggestive findings by identification of a heterozygous pathogenic (or likely pathogenic) variant in MED12 on molecular genetic testing (see Table 1).

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous MED12 variant of uncertain significance does not establish or rule out a diagnosis of an MED12-related disorder.

Note: Female carriers of a pathogenic variant in MED12 associated with FGS1 and LS have been unaffected. XLOS is typically seen in affected males and can be inherited from unaffected female carriers but females with clinical features associated with XLOS have been reported [Murakami et al 2020]. All reported individuals with Hardikar syndrome have been females with MED12 frameshift or nonsense variants [Li et al 2021]. An increasing number of females have been reported with MED12 variants that cause NSID [Polla et al 2021].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of an MED12-related disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Genotype-Phenotype Correlations

FGS1. The p.Arg961Trp and p.Gly958Glu pathogenic variants in MED12 are associated with a recognizable phenotype that includes characteristic facial features (tall forehead, frontal hair upsweep, long narrow face, open mouth), small simple ears, absolute or relative macrocephaly, congenital anomalies (corpus callosum, heart, anus, skeleton), behavior issues, and relatively nonspecific features of hypotonia, constipation, and feeding problems [Risheg et al 2007, Clark et al 2009, Rump et al 2011]. A male with suspected FGS1 was found to have a p.Asn898Asp variant in MED12 that was also identified in a male reported with NSID [Donnio et al 2017, Srivastava et al 2019].

LS. Males from three families have been reported with LS due to a p.Asn1007Ser variant in MED12 [Schwartz et al 2007, Khan et al 2016]. Two families with males who have clinical features that overlap LS have been reported with a p.Arg1295His variant in MED12 [Donnio et al 2017, Srivastava et al 2019]. Two male sibs with a p.Arg1214Cys variant in MED12 were reported with clinical features felt to overlap LS and FGS1 [Srivastava et al 2019]. A female with a p.Trp1557Arg variant in MED12 was described with clinical features felt to overlap with LS including intellectual disability, prominent nose, and short philtrum [Gonzalez et al 2021]. Features of LS that distinguish it from FGS1 include tall and thin habitus, prominent nasal bridge, high narrow palate, and short philtrum.

XLOS. Males from two families have been reported with XLOS due to a p.Arg1148His hemizygous pathogenic variant in MED12 [Vulto-van Silfhout et al 2013, Isidor et al 2014]. Two females with NSID were found to have the p.Arg1148His variant, inherited from their unaffected mother [Charzewska et al 2018]. A de novo p.Glu172Gln variant was reported in a female with XLOS and a female with NSID [Murakami et al 2020, Polla et al 2021]. XLOS and NSID have been reported in males with a p.Arg296Glu variant [Patil et al 2017, Amodeo et al 2020]. Individuals with XLOS share clinical features of intellectual disability, hypotonia, and behavior issues with FGS1 and LS but can be distinguished by the presence of blepharophimosis, ptosis, facial coarsening, and thick alae nasi [Vulto-van Silfhout et al 2013]. Corpus callosum dysgenesis and macrocephaly are not common in XLOS [Vulto-van Silfhout et al 2013, Isidor et al 2014].

HS. Seven females have been reported with unique de novo nonsense and frameshift variants in MED12. One of the affected females was reported with 15% mosaicism and no reported eye findings [Li et al 2021].

NSID. Truncating variants have been reported to cause more severe clinical features than missense variants in both males and females with NSID [Lesca et al 2013, Polla et al 2021].

Penetrance

Penetrance is presumed to be 100% in males with MED12 pathogenic variants associated with FGS1, LS, XLOS, and NSID; however, recent reports involve unique variants, and incomplete penetrance in males may be identified in the future as additional families are described.

Females with MED12 variants associated with FGS1 and LS are typically unaffected [Schwartz et al 2007, Clark et al 2009, Rump et al 2011]. Unaffected heterozygous females have been described in families with XLOS [Vulto-van Silfhout et al 2013]. However, a female was reported with XLOS [Murakami et al 2020] and two affected females and their unaffected mother were found to have the p.Arg1148His variant previously reported in males with XLOS [Charzewska et al 2018]. All females reported to have HS due to a MED12 variant have characteristic clinical features [Li et al 2021]. Affected females with variable clinical expression have been described in families with NSID [Lesca et al 2013, Bouazzi et al 2015].

Nomenclature

The name FG syndrome represents two surname initials in the originally reported family. FGS1 is also referred to as Opitz-Kaveggia syndrome [Risheg et al 2007].

Lujan syndrome is also referred to as Lujan-Fryns syndrome or intellectual disability, X-linked, with marfanoid habitus [Schwartz et al 2007].

X-linked Ohdo syndrome has been referred to as blepharophimosis and mental retardation syndrome, Maat-Kievit-Brunner type [Vulto-van Silfhout et al 2013].

Prevalence

The prevalence of FGS1 is unknown, but FGS1 appears to be an uncommon condition as only 11 families with clinical features of FGS1 have been found with a pathogenic variant in MED12 [Risheg et al 2007, Clark et al 2009, Rump et al 2011]. An additional male with suspected FGS1 was reported to have a p.Asn898Asp variant in MED12 [Srivastava et al 2019].

The prevalence of LS is unknown; it appears to be uncommon, as only three families with clinical features of LS have been found to have the p.Asn1007Ser pathogenic variant in MED12 [Schwartz et al 2007, Khan et al 2016]. Additional individuals have been reported with clinical features that overlap LS [Donnio et al 2017, Srivastava et al 2019, Gonzalez et al 2021].

The prevalence of XLOS is unknown but it appears to be uncommon with fewer than ten families reported to have XLOS due to a MED12 pathogenic variant [Vulto-van Silfhout et al 2013, Isidor et al 2014, Patil et al 2017, Murakami et al 2020, Rubin et al 2020].

The prevalence of HS is unknown with only seven affected females reported with unique frameshift and nonsense variants in MED12 [Li et al 2021].

The overall prevalence of MED12-related disorders appears to be higher than suggested by the prevalence associated with specific syndromic forms, as there are an increasing number of reported cases of NSID due to MED12 variants affecting both males and females [Charzewska et al 2018, Rubinato et al 2020, Polla et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an MED12-related disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

MED12-related disorders are inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the MED12 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the MED12 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo MED12 pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Parents of a female proband

• Because there have been no instances reported to date of a male with a pathogenic MED12 variant reproducing, an affected female proband would not be expected to have inherited the MED12 pathogenic variant from her father.
• A female proband may have inherited the MED12 pathogenic variant from her mother (who may be unaffected or have variable clinical features depending on the pathogenic variant and X-chromosome inactivation) or the pathogenic variant may be de novo. (Note: An increasing number of female probands have been reported with MED12-related nonspecific intellectual disability (NSID), with most affected female probands having the disorder as the result of a de novo pathogenic variant.)
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.

Sibs of a proband

• The risk to sibs of a male proband depends on the genetic status of the mother; the risk to sibs of a female proband is also expected to depend on the genetic status of the mother as there are no reports to date of a male with a pathogenic MED12 variant reproducing.
• If the mother of the proband has a MED12 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit a MED12 pathogenic variant will be affected.
  • Females who inherit a pathogenic variant associated with FG syndrome type 1 (FGS1) or Lujan syndrome (LS) will be heterozygotes and will typically be unaffected but may have clinical manifestations (see Clinical Description).
  • Both males and females have been reported with X-linked Ohdo syndrome (XLOS) [Vulto-van Silfhout et al 2013, Murakami et al 2020]. Females who inherit a pathogenic variant may be unaffected or have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
  • Hardikar syndrome (HS) has only been reported in females [Li et al 2021]. Females who inherit the pathogenic variant may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
  • Females with specific pathogenic variants associated with NSID may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the MED12 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the theoretic possibility of maternal germline mosaicism or, if the proband is female, paternal transmission.

Offspring of a male proband. Affected males are not known to reproduce.

Offspring of a female proband

• Females with a MED12 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy (see Sibs of a proband).
• Female probands with NSID due to specific MED12 pathogenic variants have been reported to have both affected male and female offspring [Lesca et al 2013].

Other family members. The maternal aunts and maternal cousins of a proband may be at risk of having a MED12 pathogenic variant; to date, transmission of a MED12 pathogenic variant through male family members has not been reported.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the MED12 pathogenic variant in the proband.

Females who are heterozygous for an MED12 pathogenic variant associated with FGS1 or LS are typically unaffected but may have clinical manifestations. Females have been reported with clinical features consistent with XLOS. HS is caused by pathogenic MED12 variants in females who have characteristic clinical findings. MED12 variants reported to cause NSID can result in clinical findings in heterozygous females with significant variability related to the specific variant as well as X-chromosome inactivation (see Clinical Description).

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or are at risk of being heterozygotes.

Prenatal Testing and Preimplantation Genetic Testing

Once the MED12 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MED12-related disorders are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

MED12 encodes MED12, a subunit of a protein complex called Mediator. Mediator serves as an interface between transcription factors and RNA polymerase II and comprises multiple subunits organized into a head, middle, and tail module. A fourth module (Cdk8 module), which contains MED12, can also be included in Mediator. Mediator can activate or repress transcription through specific action of the MED12 protein when the CdK8 module is present [Plassche & Brouwer 2021].

The MED12 protein contains an N-terminal MED12 domain involved in Cdk8 activation and a C-terminal Pro-, Gln-, and Leu-rich (PQL) domain which plays an important role in gene regulation through interaction with the Wnt, sonic hedgehog, REST, and SOX9 pathways [Plassche & Brouwer 2021]. The LCEWAV, LS, and OPA domains do not have known functions but the majority of reported MED12 variants involve the LS domain [Srivastava et al 2019, Plassche & Brouwer 2021].

Mechanism of disease causation. Females with Hardikar syndrome have been reported with loss-of-function variants that are predicted to be degraded by nonsense-mediated decay [Li et al 2021]. It has been suggested that males and females with nonspecific intellectual disability (NSID) due to nonsense and frameshift variants in MED12 have intellectual disability due to loss of function, with variants in the C-terminal part of the gene escaping nonsense-mediated decay [Li et al 2021, Polla et al 2021]. Splice variants with overlapping clinical features are also felt to be due to loss of function [Polla et al 2021]. Missense variants that disrupt MED12 function have been identified across the gene and can result in variable severity in males and females [Plassche & Brouwer 2021].

Author Notes

Greenwood Genetic Center

Acknowledgments

The author would like to thank Drs Roger Stevenson and Michael Friez for their critical review of the manuscript.

Revision History

• 12 August 2021 (sw) Comprehensive update posted live
• 11 August 2016 (sw) Comprehensive update posted live
• 6 June 2013 (me) Comprehensive update posted live
• 14 July 2009 (cd) Revision: targeted mutation analysis for p.Arg961Trp mutation available clinically
• 23 June 2008 (me) Review posted live
• 25 April 2008 (mjl) Original submission

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