Clinical characteristics.

MED13L syndrome is characterized by mild-to-profound developmental delay, intellectual disability, and hypotonia. Neurobehavioral manifestations (autistic features, agitation/aggression, restlessness, self-harm, tantrums, frustration, overfriendliness, and/or hyperactivity) are also reported. Some individuals have abnormal findings on brain imaging (ventriculomegaly, delayed or lack of myelination, thin or absent corpus callosum, periventricular foci, and/or subcortical white matter abnormalities). Dysmorphic facial features, including depressed nasal bridge, bulbous nose, and hypotonic open mouth, are present in most individuals. Distal limb and/or digit anomalies, ocular manifestations and vision issues, and congenital heart defects have been reported. Other reported features include seizures and/or hearing impairment.

Diagnosis/testing.

The diagnosis of MED13L syndrome is established in a proband with a heterozygous pathogenic variant in MED13L identified by molecular genetic testing.

Management.

Treatment of manifestations: Standardized treatment for developmental, intellectual, and behavioral issues and seizures; treatment of orthopedic manifestations, congenital heart disease, and ocular manifestations per relevant specialist; hearing aids may be helpful per otolaryngologist; community hearing services through early intervention or the school district; treatment of neonatal respiratory issues per intensivist and/or pulmonologist; feeding therapy; gastrostomy tube placement as needed; social work and family support.

Surveillance: Monitor developmental progress, educational needs, behavior issues, and development of or changes in seizures at each visit; assessment of mobility and self-help skills at each visit; clinical assessment for scoliosis at each visit with radiographs as needed; assess for changes in visual acuity and strabismus per treating ophthalmologist; audiology evaluation annually or as needed; monitor for evidence of aspiration and/or respiratory insufficiency, nutritional status, safety of oral intake, and family needs at each visit.

Genetic counseling.

MED13L syndrome is an autosomal dominant disorder. The majority of probands reported to date whose parents have undergone molecular genetic testing have the disorder as the result of a pathogenic variant that occurred as a de novo event in the proband. Rarely, individuals diagnosed with MED13L syndrome have the disorder as the result of a pathogenic variant inherited from a mosaic, apparently unaffected parent. Once the MED13L pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

MED13L syndrome should be considered in probands with the following clinical and brain MRI findings and family history.

Clinical findings

• Mild-to-profound developmental delay
• Intellectual disability of variable degree
• Hypotonia
• Neurobehavioral manifestations
• Facial dysmorphisms. Depressed nasal bridge and bulbous nose, broad forehead, frontal bossing, up- or down-slanted palpebral fissures, large, low-set ears with prominent antihelix stem, short and deep philtrum, exaggerated Cupid's bow, macroglossia with hypotonic open mouth and/or tongue protrusion, and cleft or highly arched palate (See Figure 1.)
• Musculoskeletal features, ophthalmologic involvement, congenital heart defects, and seizures in some individuals

Figure 1.

Characteristic facial features of individuals with MED13L syndrome (a, b) Female age 22 years with low columella, short philtrum, retrognathia, and prominent antihelix stem

Brain MRI findings

• Ventriculomegaly (9/62 individuals)
• Delayed or lack of myelination (6/62)
• Thin or absent corpus callosum (5/62)
• Periventricular foci and subcortical white matter abnormalities (7/62)

Family history. Because MED13L syndrome is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of MED13L syndrome is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in MED13L identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous MED13L variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome or genome sequencing [Manickam et al 2021, van der Sanden et al 2023]. Other options include use of a multigene panel. Note: Single-gene testing (sequence analysis of MED13L, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome and genome sequencing is widely used and yields results similar to an intellectual disability multigene panel, with the additional advantage that exome and genome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. To date, the majority of MED13L pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome or genome sequencing.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• An intellectual disability multigene panel that includes MED13L and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of MED13L syndrome, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

MED13L syndrome is characterized by developmental delay, intellectual disability, hypotonia, and often behavioral abnormalities. Characteristic facial features have been described. Some individuals have distal limb and/or digit anomalies, ocular manifestations and/or vision defects, and/or congenital heart defects. To date, more than 100 published individuals have been identified with a pathogenic variant in MED13L. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay. Developmental delay is reported in all individuals. This can range from mild to profound and can affect various developmental domains.

Hypotonia is common. Some individuals have facial hypotonia, including an open mouth and protruding tongue [Adegbola et al 2015, van Haelst et al 2015, Asadollahi et al 2017]. Delayed head control is reported during infancy [Caro-Llopis et al 2016]. The range of age for sitting without assistance is 8 months to 17 months. Most individuals become ambulatory. The range in age in those that achieve walking without assistance is 20 months to 3.5 years. Some individuals walk only with assistance, and some do not become ambulatory.

Speech and language development is delayed or completely lacking in most individuals (99%). Several individuals are able to follow short commands but lack expressive language [Asadollahi et al 2013].

Intellectual disability. Intellectual disability is reported in all individuals; this includes specific learning disabilities. This ranges from mild (fewer than 10%) to severe (15%), with the majority of individuals reported as having moderate disability. Most require specialized education programs. Some individuals progress to relative independence with educational support [Muncke et al 2003, Utami et al 2014, Adegbola et al 2015, Caro-Llopis et al 2016, Asadollahi et al 2017, Smol et al 2018, Carvalho et al 2021, Bessenyei et al 2022].

Neurobehavioral manifestations. Roughly 60% of individuals have behavioral issues. Autistic features are the most common. Agitation/aggression, restlessness, self-harm, tantrums, frustration, overfriendliness, and hyperactivity have also been reported. Individuals may have bursts of energy and then tire easily.

Seizures are reported in 22% of individuals. The types of seizures reported include absence seizures and febrile seizures; however, due to low numbers reported, no seizure subtype patterns can be discerned. Some individuals had epileptiform discharges on EEG; however, this is not a common feature. Of those individuals reported with seizures, the seizures are managed with anti-seizure medications.

Other neurologic manifestations. Ataxia was reported in 9/25 individuals and mainly consisted of dynamic ataxia. The average age of individuals with ataxia was 12 years, but no age of onset has been reported. Dysarthria was reported in 4/9 individuals, who all presented with this manifestation.

Brain MRI findings have been reported for 33 individuals. These findings included ventriculomegaly (n=9), white matter abnormalities (n=7), myelination defects (n=6), and corpus callosum thinning or agenesis (n=5).

Characteristic facial features (see Figure 1). Many individuals have a distinct depressed nasal bridge and bulbous nose (>75%). Additional common features include broad forehead, frontal bossing, up- or down-slanted palpebral fissures, large, low-set ears with prominent antihelix stem, short and deep philtrum, exaggerated Cupid's bow, cleft or high-arched palate, and macroglossia. Less common features include brachycephaly (7%), flat occiput (<1%), and plagiocephaly (3%) [Adegbola et al 2015, Asadollahi et al 2017].

Musculoskeletal features. Manifestations in the lower extremities can include clubfoot (10%), metatarsus varus (6%), and abnormalities of the toes including clinodactyly (10%), syndactyly (7%), and camptodactyly (3%). Abnormalities of the hands can include decreased palmar creases, extra phalangeal creases (5%), and/or radial clubhand (<1%). The most common spine abnormality is scoliosis (5%).

Ophthalmologic involvement. The most common ocular abnormality is strabismus (31 individuals). Other ocular manifestations include Duane anomaly and nystagmus. Myopia, hyperopia, and astigmatism have also been reported [Adegbola et al 2015, Caro-Llopis et al 2016].

Congenital heart disease. Approximately 20% (22/94) of individuals reported have congenital heart defects, including patent foramen ovale (10%), perimembranous ventricular septal defect (6%), dextro-looped transposition of the great arteries (5%), and mild coarctation of the aorta (5%).

Hearing impairment. Sensorineural and conductive hearing loss have been reported in 6% of persons with MED13L syndrome [Adegbola et al 2015, Cafiero et al 2015, Caro-Llopis et al 2016, Smol et al 2018]. The age of onset of hearing loss has not been reported.

Respiratory abnormalities. One infant had asphyxia at birth [Yi et al 2020]. Respiratory distress has been reported in some neonates. One infant required oxygen therapy, while another was intubated for six days. In most individuals, respiratory issues did not persist beyond infancy [Cafiero et al 2015, Caro-Llopis et al 2016]. One infant had persistent respiratory infections including pneumonia, but respiratory function significantly improved by age six years.

Gastrointestinal manifestations. Gastrointestinal reflux during infancy, leading to feeding problems, has been reported in 2% of infants. Frequent vomiting is uncommon but has been reported [Asadollahi et al 2013, van Haelst et al 2015, Asadollahi et al 2017]. Abnormal positioning of the anus has been reported in three individuals (either posteriorly or anteriorly) [Asadollahi et al 2013, Adegbola et al 2015]. Both inguinal and umbilical hernias have been reported (10%) [Adegbola et al 2015, Gordon et al 2018, Smol et al 2018, Tørring et al 2019].

Genitourinary abnormalities. Cryptorchidism (8%) [Adegbola et al 2015, Caro-Llopis et al 2016] and micropenis (2%) have both been reported [Gordon et al 2018, Smol et al 2018]. Congenital ureteropelvic junction obstruction (<1%) [Yi et al 2020], hydroureter (<1%) [Tørring et al 2019], kidney cysts (<1%) [Smol et al 2018], and renal agenesis (<1%) have all been rarely reported [Caro-Llopis et al 2016]. In addition, some individuals had delayed bladder control or persistent urinary incontinence [Asadollahi et al 2013].

Growth. Most individuals have normal growth parameters at birth including head circumference, weight, and length. Microcephaly (2%) and macrocephaly (<1%) are rarely reported.

Prognosis. Based on current data, life span is not limited by this condition, as several adults have been reported. Data on possible progression of behavior abnormalities or neurologic findings are still limited.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified; however, pathogenic missense variants appear to be associated with more severe manifestations, including severe motor delay, seizures, and autism / behavioral issues. A higher likelihood of absent speech (5/9), absent ambulation (4/9), seizures (5/9), and autistic features (5/8) were reported in individuals with MED13L pathogenic missense variants compared to other variant types [Smol et al 2018]. These missense variants have been located in exons 15 through 17 and exons 25 through 31. These correlations are still not completely understood and require further testing.

Penetrance

There are no reported individuals with a MED13L pathogenic variant that do not have manifestations of the disorder; therefore, penetrance is complete.

Prevalence

To date, more than 100 published individuals have been identified with a pathogenic variant in MED13L. The authors are aware of many additional affected individuals, and prevalence is likely higher than suggested by the number of individuals reported in the literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MED13L syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric/adult neurology, occupational therapy, audiology, speech-language pathology, clinical genetics, orthopedics, physical therapy, and mental health (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

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

MED13L syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• The majority of probands reported to date with MED13L syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a MED13L pathogenic variant that occurred as a de novo event in the proband.
• Rarely, individuals diagnosed with MED13L syndrome have the disorder as the result of a MED13L pathogenic variant inherited from a mosaic, apparently unaffected parent [Yamamoto et al 2017, Smol et al 2018, Bessenyei et al 2022].
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an MED13L pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the MED13L pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Transmission of a MED13L pathogenic variant from a heterozygous parent to an affected child has not been reported to date.
• If the MED13L pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism. Transmission of a MED13L pathogenic variant from a mosaic parent to affected sibs has been reported in several families [Yamamoto et al 2017, Smol et al 2018, Bessenyei et al 2022].

Offspring of a proband. Each child of an individual with MED13L syndrome has a 50% chance of inheriting the MED13L pathogenic variant; to date, individuals with MED13L syndrome are not known to reproduce.

Other family members. Given that all probands with MED13L syndrome reported to date have the disorder as a result of an MED13L pathogenic variant that occurred de novo in the proband or in a mosaic parent, the risk to other family members is presumed to be low.

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 parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the MED13L pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

MED13L encodes mediator of RNA polymerase II transcription subunit 13-like (MED13L), which along with its paralog MED13 are interchangeable subunits of the CDK8-kinase module (CKM) [Knuesel et al 2009]. The CKM, composed of either protein paralog, is associated with the larger mediator complex that is responsible for controlling RNA polymerase II-dependent transcription [Chang et al 2022]. MED13L and MED13 serve as a protein tether for the CKM to the mediator. Additional members of the CKM include cyclin C, CDK8, CDK19, MED12, and MED12L [Knuesel et al 2009, Ježek et al 2019]. As MED13L and MED13 play a major role in the mediator complex, necessary for transcription of almost all RNA polymerase II-dependent genes, MED13L pathogenic variants cause known transcriptional defects [Chang et al 2022].

Studies have also shown that MED13L pathogenic variants lead to mislocalization of cyclin C [Chang et al 2022]. Cyclin C has been extensively characterized for its role in mitochondrial fragmentation within the cell [Chang et al 2022].

Mechanism of disease causation. Reports suggest that MED13L syndrome is the result of MED13L haploinsufficiency. A dominant-negative effect cannot be ruled out, and further studies are necessary to confirm disease causation. It is also possible that some variants have a gain-of-function effect. This could potentially provide an explanation for the more severe phenotype associated with MED13L missense pathogenic variants.

Author Notes

Dr Alicia Campbell is actively involved in clinical and molecular biology research regarding individuals with MED13L syndrome. For those with questions regarding molecular and genetic work for MED13L syndrome, reach out via email (ude.nawor@62ebpmac).

If there are questions related to diagnosis/management of MED13L syndrome, contact Dr Jennifer Bain (ude.aibmuloc.cmuc@4363bj), who sees patients with MED13L syndrome.

Additionally, contact Dr Reza Asadollahi (ku.ca.hciwneerg@ihallodasa.r), who actively sees patients with MED13L syndrome, and whose research has laid much of the foundation for clinicians caring for those with MED13L syndrome today.

Contact any of those listed above to inquire about review of MED13L variants of uncertain significance.

Acknowledgments

The authors would like to acknowledge the MED13L Foundation for all initiatives regarding clinical accessibility and increasing awareness of MED13L syndrome. Additionally, the authors would like to thank members of the Strich/Cooper lab, specifically Dr Steven Doyle, for his insight into diagnosis and management.

Revision History

• 10 April 2025 (sw) Review posted live
• 2 May 2024 (ac) Original submission

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