Clinical Guidance

FGS1. The and 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 . A male with suspected FGS1 was found to have a variant in MED12 that was also identified in a male reported with NSID . LS. Males from three families have been reported with LS due to a variant in MED12 . Two families with males who have clinical features that overlap LS have been reported with a variant in MED12 .

Source: GeneReviews — "MED12-Related Disorders"

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 . Unaffected heterozygous females have been described in families with XLOS . However, a female was reported with XLOS and two affected females and their unaffected mother were found to have the variant previously reported in males with XLOS . All females reported to have HS due to a MED12 variant have characteristic clinical features . Affected females with variable clinical expression have been described in families with NSID .

Source: GeneReviews — "MED12-Related Disorders"

Diagnostic Criteria

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:

Source: GeneReviews — "MED12-Related Disorders"

Differential Diagnosis

Disorders with features overlapping those of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS) and/or Hardikar syndrome (HS) are summarized in .

Table 2.

Disorders to Consider in the Differential Diagnosis of FG Syndrome Type 1, Lujan Syndrome, X-Linked Ohdo Syndrome, and Hardikar Syndrome

Gene /Genetic Mechanism | Disorder | MOI | Clinical Overlap with:

FGS1 | LS | XLOS | HS

CBS | Homocystinuria | AR | + |

CHD7 | CHARGE syndrome (See CHD7 Disorder.) | AD |

+

CREBBP

EP300

| Rubinstein-Taybi syndrome | AD | + |

FBN1 | Marfan syndrome | AD | + |

FLNA | FG syndrome 2 (OMIM 300321) | XL | + |

FMR1 | Fragile X syndrome | XL | + | + |

FOLX23q23 rearrangements | Blepharophimosis, ptosis, epicanthus inversus syndrome | AD(AR) |

+ |

Source: GeneReviews — "MED12-Related Disorders"

Management Guidelines

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

Source: GeneReviews — "MED12-Related Disorders"

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.

Source: GeneReviews — "MED12-Related Disorders"

Surveillance Guidelines

Table 5. Recommended Surveillance for Individuals with MED12-Related Disorders

Source: GeneReviews — "MED12-Related Disorders"