Clinical characteristics.

MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues, and cardiac manifestations. Individuals who are able to speak typically only use a few words and are not able to communicate in sentences. Approximately half of individuals are unable to walk independently; however, many are able to walk with some assistance.

Diagnosis/testing.

The diagnosis of MEF2C-related disorder is established in a proband by identification of a heterozygous pathogenic variant in MEF2C by molecular genetic testing.

Management.

Treatment of manifestations: Developmental and educational services; treatment of gait abnormalities per orthopedist, physical medicine and rehabilitation specialist, and/or physical or occupational therapist; feeding support as needed; standard treatment for gastroesophageal reflux disease, constipation, and seizures; treatment of cardiac manifestations per cardiologist; treatment of refractive errors and strabismus per ophthalmologist; more complex findings or treatment per ophthalmic subspecialist; antibiotics as needed for recurrent respiratory infections and recurrent otitis media; referral to otolaryngologist for tympanostomy tubes as needed for recurrent otitis; family and social work support.

Surveillance: At each visit, assess developmental progress, educational needs, gait issues, motor abnormalities, growth parameters, nutritional status, safety of oral intake, gastroesophageal reflux disease, and constipation; assess new or changing seizures, tone, and movement disorders at each visit or per neurologist; annual behavioral assessment; cardiology assessment per cardiologist; ophthalmology evaluation for strabismus and refractive errors per ophthalmologist; assessment for recurrent respiratory infections and/or recurrent otitis media annually or as needed; hearing evaluation in those with recurrent otitis annually or as needed; assess family needs at each visit.

Genetic counseling.

MEF2C-related disorder is an autosomal dominant disorder. Most probands reported to date with MEF2C-related disorder whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Rarely, a proband diagnosed with MEF2C-related disorder has the disorder as the result of a pathogenic variant inherited from an affected heterozygous parent or an unaffected mosaic parent. Each child of an individual with MEF2C-related disorder has a 50% chance of inheriting the pathogenic variant. Once the MEF2C pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

MEF2C-related disorder should be considered in probands with the following clinical and brain MRI findings and family history.

Clinical findings

• Moderate-to-profound developmental delay (including lack of speech in 95% and inability to walk independently in 50%)
• Profound intellectual disability
• Hypotonia
• Feeding/gastrointestinal issues (constipation, gastroesophageal reflux disease, feeding difficulties)
• Dysmorphic facial features (broad forehead, prominent philtrum, tented upper lip, widely spaced teeth, large ears)
• Seizures (febrile, infantile spasms, generalized tonic-clonic, myoclonic, and focal)
• Neurobehavioral/psychiatric manifestations, including autistic features (decreased social interaction, stereotypic movements particularly of the hands, repetitive rocking and head shaking, hyperkinesis), bruxism, agitation, sleep issues, and high pain tolerance
• Cardiac manifestations (ventricular septal defect, double outlet right ventricle, patent ductus arteriosus, pulmonary stenosis, and adult-onset dilated cardiomyopathy)
• Vison issues (strabismus, refractive errors)

Brain MRI findings

• Hypoplastic corpus callosum
• Mild thinning of the cortical white matter
• Enlarged ventricles and other cerebrospinal fluid spaces (including the subarachnoid space and cortical sulcus)
• Delay in myelination and mild undermyelination

Family history. Because MEF2C-related disorder is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of MEF2C-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in MEF2C 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 MEF2C 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 sequencing 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 MEF2C, 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 sequencing is most commonly used and yields results similar to an intellectual disability multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• An intellectual disability, autism, or epilepsy/seizure multigene panel that includes MEF2C and other genes of interest (see Differential Diagnosis) may also be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants 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 MEF2C-related disorder, some panels for intellectual disability, autism, or epilepsy/seizures 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

MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, lack of speech or speech impairment, limited walking, hypotonia, feeding and gastrointestinal issues, dysmorphic features, seizures, neurobehavioral manifestations including autistic features, cardiac manifestations, and vision issues. Individuals who are able to speak typically only use a few words and are not able to communicate in sentences. Approximately half of individuals are unable to walk independently; however, many are able to walk with some assistance [Cooley Coleman et al 2021]. To date, 142 individuals have been identified with a pathogenic variant in MEF2C including large deletions of all or part of MEF2C [Stenson et al 2020, Cooley Coleman et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay and intellectual disability. Developmental delay is evident early in life with both speech and motor delays. Most affected individuals are unable to speak but may use some vocalizations or babble. Those who are able to speak typically only use a few words and are not able to form sentences. Most individuals are able to reach for objects and transfer them from hand to hand, but acquisition of fine motor skills (e.g., pincer grasp and using utensils for feeding) are less common. Hypotonia is a common feature and likely contributes to motor delay. Approximately half of individuals are able to walk, with this milestone being achieved between ages 16 months and six years [Cooley Coleman et al 2022]. For individuals able to walk, gait abnormalities are common.

Regression after acquiring milestones is not common in individuals with MEF2C-related disorder; however, five of 108 individuals were reported to have regression. Additionally, one individual has been reported with frontotemporal dementia in their sixth decade of life [Adrião et al 2022].

Feeding and gastrointestinal issues. Some individuals require assisted feedings. Problems with chewing and swallowing are reported. Gastroesophageal reflux disease and constipation have been common in several individuals.

Dysmorphic features. Many individuals have distinctive facial features that may include a broad forehead, thick eyebrows, deep-set eyes, large ears with prominent ear lobes, depressed nasal bridge, short and prominent philtrum, full vermilion of the upper and lower lips with tented upper lip and everted lower lip, widely spaced teeth, down-turned corners of the mouth, and micrognathia. One individual had right question mark-shaped ear and left ear dysplasia.

Epilepsy. Seizures are reported in up to 86% of affected individuals. The most reported types of seizures include febrile and myoclonic seizures. Tonic-clonic, focal, absence, afebrile, atonic, and infantile spasms are also reported. Seizure onset is within the first year of life for a majority of individuals. EEG findings include multiple epileptiform discharges, hypsarrhythmia, temporal and occipital spike-slow waves, focal or multifocal bilateral spikes, and slowing background.

Neurobehavioral/psychiatric manifestations. Many affected individuals are reported to have autistic features, some of which include lack of eye contact, lack of a social smile, lack of interest in surroundings, or limited social interactions. Several individuals display stereotypical movements, particularly of the hands, including hand clapping, hand wringing, and hand mouthing; bruxism, repetitive rocking, and head shaking are also reported. Hyperkinesis with constant movements of the hands and feet is reported in some individuals [Mikhail et al 2011, Paciorkowski et al 2013, Rocha et al 2016]. A few individuals are reported as being easily agitated and exhibiting self-mutilating behaviors including self-biting. Additional reported behavior manifestations include overstuffing the mouth when self-feeding, happy demeanor, fascination with water, and breath-holding or hyperventilation [Vrečar et al 2017, Wang et al 2018]. Some individuals have issues with sleep, including irregular sleep initiation and sleep disruption. High pain tolerance is reported in several individuals.

Cardiac manifestations. Some individuals were reported to have congenital heart defects, including ventricular septal defect, double outlet right ventricle, patent ductus arteriosus, pulmonary stenosis, and adult-onset dilated cardiomyopathy.

Growth. A few individuals were reported to have a small head circumference (2-3 standard deviations below the mean), and some (fewer than 10%) were characterized as microcephalic. Other growth parameters are typically within the normal range.

Ophthalmologic involvement. The most common reported vision issue is strabismus. One individual had bilateral esotropia, which was surgically repaired [Shim et al 2015]. Additional findings include refractive errors (e.g., myopia, hypermetropia).

Neuroimaging. Abnormalities identified on brain MRI include hypoplastic corpus callosum, mild thinning of the cortical white matter, cortical atrophy, enlarged ventricles and other cerebrospinal fluid spaces (including the subarachnoid space and cortical sulcus), Chiari I malformation, spots of nonspecific hyperintensity, delay in myelination, and mild undermyelination.

Recurrent infections, particularly upper respiratory tract infections, have been reported in several individuals. A few individuals had recurrent otitis media, some requiring tympanostomy tubes. One study, using cells from MEF2C-haploinsufficient individuals and mice, showed defects in natural killer cell development and effector function and an increased susceptibility to viral infection [Li et al 2024].

Other. Findings reported in one or only a few individuals include:

• Duplex left kidney [Vrečar et al 2017]
• Tremors [Nowakowska et al 2010, Paciorkowski et al 2013]

Prognosis. It is unknown whether life span in individuals with MEF2C-related disorder is abnormal. A number of adults with MEF2C-related disorder have been described. The oldest individual was reported alive at age 69 years [Adrião et al 2022]. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

At least two individuals with a deletion encompassing only MEF2C exons 1-3 presented with cutaneous vascular malformations, suggesting a possible genotype-phenotype correlation [Tanteles et al 2015, Vrečar et al 2017].

Individuals with pathogenic variants affecting the proximal region of the MEF2C protein (e.g., within the MADS or MEF2 domains) may be more severely affected than individuals with more distal pathogenic variants [Wang et al 2018].

Possible genotype-phenotype correlations associated with MEF2C (e.g., variant type or variant position) require further study. Note: Several reported MEF2C genotype-phenotype correlations compare MEF2C single-nucleotide variants to larger contiguous deletions that encompass additional genes; these are not included in this GeneReview.

Penetrance

Penetrance is 100%; all individuals who have a MEF2C pathogenic variant have clinical manifestations of the disorder. There have been no reports of unaffected individuals with a pathogenic variant in MEF2C.

Nomenclature

The term "MEF2C-related neurodevelopmental disorder" is based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Prevalence

The prevalence of MEF2C-related disorder is unknown. At least 142 affected individuals have been reported in the literature to date. Eight additional affected individuals are known to the authors but have not been reported in the medical literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MEF2C-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for MEF2C-related disorder. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in developmental behavior, neurology, ophthalmology, and cardiology (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

MEF2C-related disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with MEF2C-related disorder whose parents have undergone molecular genetic testing have the disorder as the result of a de novo MEF2C pathogenic variant.
• Rarely, a proband diagnosed with MEF2C-related disorder has the disorder as the result of an MEF2C pathogenic variant inherited from a:
  • Heterozygous parent. Transmission of a MEF2C pathogenic variant from an affected parent has been reported in three families. Affected individuals in these families had intellectual disability, seizures, speech impairment, stereotypic movements, and cardiac manifestations [Qiao et al 2017, Lu et al 2018, Yuan et al 2018].
  • Parent with gonadal (or somatic and gonadal) mosaicism. Transmission of an MEF2C pathogenic variant from an unaffected mosaic parent to a child with MEF2C-related disorder has been reported in two families to date [Wan et al 2021].
• 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.

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 MEF2C pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the MEF2C pathogenic variant identified 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 [Wan et al 2021].

Offspring of a proband.

• Each child of an individual with MEF2C-related disorder has a 50% chance of inheriting the MEF2C pathogenic variant.
• The majority of individuals with MEF2C-related disorder are not known to reproduce; however, many are not yet of reproductive age.

Other family members. Given that the majority of individuals with MEF2C-related disorder reported to date have the disorder as the result of an MEF2C pathogenic variant that occurred de novo in the proband or 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 MEF2C 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

MEF2C encodes myocyte-specific enhancer factor 2C (MEF2C), a member of the MADS family of transcription factors, which regulate hundreds of downstream gene targets during development and adulthood. MEF2C is particularly crucial during embryogenesis, as it plays a role in myogenesis, neural crest formation, anterior heart field development, lymphoid development, neurogenesis, and synaptic formation, among other functions. MEF2C haploinsufficiency occurs when MEF2C pathogenic variants (including loss of function and missense) produce abnormal gene products that cannot bind DNA targets properly, as shown by functional studies of some variants that cause MEF2C-related disorder [Harrington et al 2020]. MEF2C hypofunction in neurons is presumed to underlie most of the symptoms of MEF2C-related disorder.

Mechanism of disease causation. Loss of function, haploinsufficiency

MEF2C-specific laboratory technical considerations. In addition to deletions and coding region variants, pathogenic deep intronic variants have been reported [Wright et al 2021, Adrião et al 2022]. Certain genetic testing methods may not be able to detect these variants.

Author Notes

Dr Jessica Cooley Coleman (gro.cgg@namelocj) became involved with MEF2C research during her doctoral studies by scouring the scientific literature and developing a parent survey to better characterize the disorder. She seeks to remain knowledgeable and involved in MEF2C research when possible. She would be happy to communicate with persons who have any questions regarding diagnosis of MEF2C-related disorder or other considerations.

Dr Steven A Skinner (gro.cgg@sas) would be happy to communicate with persons who have any questions regarding diagnosis of MEF2C-related disorder or other considerations. Contact him to inquire about potential clinical evaluations or possibilities for functional evaluation of all MEF2C variants of uncertain significance.

Contact Dr Cooley Coleman to inquire about review of MEF2C variants of uncertain significance.

Acknowledgments

The authors would like to thank all individuals with MEF2C-related disorder and their families for sharing their medical and personal stories and being involved in patient support groups and research publications.

Literature Cited

• Adrião A, Santana I, Ribeiro C, Cancela ML, Conceição N, Grazina M. Identification of a novel mutation in MEF2C gene in an atypical patient with frontotemporal lobar degeneration. Neurol Sci. 2022;43:319-26. [PubMed: 33999292]
• Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, Bennett JT, Bird LM, Carey JC, Chung B, Clark RD, Cox TC, Curry C, Dinulos MBP, Dobyns WB, Giampietro PF, Girisha KM, Glass IA, Graham JM Jr, Gripp KW, Haldeman-Englert CR, Hall BD, Innes AM, Kalish JM, Keppler-Noreuil KM, Kosaki K, Kozel BA, Mirzaa GM, Mulvihill JJ, Nowaczyk MJM, Pagon RA, Retterer K, Rope AF, Sanchez-Lara PA, Seaver LH, Shieh JT, Slavotinek AM, Sobering AK, Stevens CA, Stevenson DA, Tan TY, Tan WH, Tsai AC, Weaver DD, Williams MS, Zackai E, Zarate YA. A dyadic approach to the delineation of diagnostic entities in clinical genomics. Am J Hum Genet. 2021;108:8-15. [PMC free article: PMC7820621] [PubMed: 33417889]
• Cooley Coleman JA, Sarasua SM, Boccuto L, Moore HW, Skinner SA, DeLuca JM. Comprehensive investigation of the phenotype of MEF2C-related disorders in human patients: A systematic review. Am J Med Genet A. 2021;185:3884-94. [PubMed: 34184825]
• Cooley Coleman JA, Sarasua SM, Moore HW, Boccuto L, Cowan CW, Skinner SA, DeLuca JM. Clinical findings from the landmark MEF2C-related disorders natural history study. Mol Genet Genomic Med. 2022;10:e1919. [PMC free article: PMC9184670] [PubMed: 35416405]
• Harrington AJ, Bridges CM, Berto S, Blankenship K, Cho JY, Assali A, Siemsen BM, Moore HW, Tsvetkov E, Thielking A, Konopka G, Everman DB, Scofield MD, Skinner SA, Cowan CW. MEF2C hypofunction in neuronal and neuroimmune populations produces MEF2C haploinsufficiency syndrome-like behaviors in mice. Biol Psychiatry. 2020;88:488-99. [PMC free article: PMC7483399] [PubMed: 32418612]
• Li JH, Zhou A, Lee CD, Shah SN, Ji JH, Senthilkumar V, Padilla ET, Ball AB, Feng Q, Bustillos CG, Riggan L, Greige A, Divakaruni AS, Annese F, Cooley Coleman JA, Skinner SA, Cowan CW, O'Sullivan TE. MEF2C regulates NK cell effector functions through control of lipid metabolism. Nat Immunol. 2024;25:778-89. [PubMed: 38589619]
• Lu CX, Wang W, Wang Q, Liu XY, Yang YQ. A novel MEF2C loss-of-function mutation associated with congenital double outlet right ventricle. Pediatric cardiology. 2018;39:794–804. [PubMed: 29468350]
• Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, Massingham LJ, Miller D, Yu TW, Hisama FM, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:2029-37. [PubMed: 34211152]
• Mikhail FM, Lose EJ, Robin NH, Descartes MD, Rutledge KD, Rutledge SL, Korf BR, Carroll AJ. Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders. Am J Med Genet A. 2011;155A:2386-96. [PubMed: 22031302]
• Nowakowska BA, Obersztyn E, Szymańska K, Bekiesińska-Figatowska M, Xia Z, Ricks CB, Bocian E, Stockton DW, Szczałuba K, Nawara M, Patel A, Scott DA, Cheung SW, Bohan TP, Stankiewicz P. Severe mental retardation, seizures, and hypotonia due to deletions of MEF2C. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:1042-51. [PubMed: 20333642]
• Paciorkowski AR, Traylor RN, Rosenfeld JA, Hoover JM, Harris CJ, Winter S, Lacassie Y, Bialer M, Lamb AN, Schultz RA, Berry-Kravis E, Porter BE, Falk M, Venkat A, Vanzo RJ, Cohen JS, Fatemi A, Dobyns WB, Shaffer LG, Ballif BC, Marsh ED. MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways. Neurogenetics. 2013;14:99-111. [PMC free article: PMC3773516] [PubMed: 23389741]
• Qiao XH, Wang F, Zhang XL, Huang RT, Xue S, Wang J, Qiu XB, Liu XY, Yang YQ. MEF2C loss-of-function mutation contributes to congenital heart defects. Int J Med Sci. 2017;14:1143–53. [PMC free article: PMC5666546] [PubMed: 29104469]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rocha H, Sampaio M, Rocha R, Fernandes S, Leão M. MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review. Eur J Med Genet. 2016;59:478-82. [PubMed: 27255693]
• Shim JS, Min K, Lee SH, Park JE, Park SH, Kim M, Shim SH. MEF2C-related 5q14.3 microdeletion syndrome detected by array CGH: a case report. Ann Rehabil Med. 2015;39:482-7. [PMC free article: PMC4496521] [PubMed: 26161356]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Tanteles GA, Alexandrou A, Evangelidou P, Gavatha M, Anastasiadou V, Sismani C. Partial MEF2C deletion in a Cypriot patient with severe intellectual disability and a jugular fossa malformation: review of the literature. Am J Med Genet A. 2015;167A:664-9. [PubMed: 25691421]
• van der Sanden BPGH, Schobers G, Corominas Galbany J, Koolen DA, Sinnema M, van Reeuwijk J, Stumpel CTRM, Kleefstra T, de Vries BBA, Ruiterkamp-Versteeg M, Leijsten N, Kwint M, Derks R, Swinkels H, den Ouden A, Pfundt R, Rinne T, de Leeuw N, Stegmann AP, Stevens SJ, van den Wijngaard A, Brunner HG, Yntema HG, Gilissen C, Nelen MR, Vissers LELM. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders. Eur J Hum Genet. 2023;31:81-8. [PMC free article: PMC9822884] [PubMed: 36114283]
• Vrečar I, Innes J, Jones EA, Kingston H, Reardon W, Kerr B, Clayton-Smith J, Douzgou S. Further clinical delineation of the MEF2C haploinsufficiency syndrome: report on new cases and literature review of severe neurodevelopmental disorders presenting with seizures, absent speech, and involuntary movements. J Pediatr Genet. 2017;6:129-41. [PMC free article: PMC5548525] [PubMed: 28794905]
• Wan L, Liu X, Hu L, Chen H, Sun Y, Li Z, Wang Z, Lin Z, Zou L, Yang G. Genotypes and phenotypes of MEF2C haploinsufficiency syndrome: new cases and novel point mutations. Front Pediatr. 2021;9:664449. [PMC free article: PMC8155578] [PubMed: 34055696]
• Wang J, Zhang Q, Chen Y, Yu S, Wu X, Bao X, Wen Y. Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation. BMC Med Genet. 2018;19:191. [PMC free article: PMC6208086] [PubMed: 30376817]
• Wright CF, Quaife NM, Ramos-Hernández L, Danecek P, Ferla MP, Samocha KE, Kaplanis J, Gardner EJ, Eberhardt RY, Chao KR, Karczewski KJ, Morales J, Gallone G, Balasubramanian M, Banka S, Gompertz L, Kerr B, Kirby A, Lynch SA, Morton JEV, Pinz H, Sansbury FH, Stewart H, Zuccarelli BD; Genomics England Research Consortium; Cook SA, Taylor JC, Juusola J, Retterer K, Firth HV, Hurles ME, Lara-Pezzi E, Barton PJR, Whiffin N. Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms. Am J Hum Genet. 2021;108:1083-94. [PMC free article: PMC8206381] [PubMed: 34022131]
• Yuan F, Qiu ZH, Wang XH, Sun YM, Wang J, Li RG, Liu H, Zhang M, Shi HY, Zhao L, Jiang WF, Liu X, Qiu XB, Qu XK, Yang YQ. MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy. Clin Chem Lab Med. 2018;56:502-11. [PubMed: 28902616]