Mental Retardation, Autosomal Dominant 20

A number sign (#) is used with this entry because autosomal dominant mental retardation syndrome-20 (MRD20) is caused by heterozygous mutation in the MEF2C gene (600662) on chromosome 5q14.3. Heterozygous deletion of the chromosome 5q14.3 region can result in the same phenotype.

Clinical Features

Sobreira et al. (2009) reported an 11-year-old boy with moderate intellectual disability, attention deficit-hyperactivity disorder, bilateral iris coloboma, hearing loss, dental anomaly, and dysmorphic facial features associated with a 7.4-Mb deletion on chromosome 5q14.3-q21.1 (see CYTOGENETICS below). Additional features included short stature, downslanting palpebral fissures, small optic nerves, cup-shaped ears, brachydactyly of the hands, and small feet. The dental anomaly was a misplacement of frontal and lateral incisors. Brain MRI showed a mild delay in myelination, but no structural brain defects.

Le Meur et al. (2010) reported 5 unrelated children, ranging in age from 9 months to 8 years, with severe mental retardation, absent speech, hypotonia, poor eye contact, and stereotypic movements associated with a deletion of chromosome 5q14. Dysmorphic features included high broad forehead with variable small chin, short nose with anteverted nares, large open mouth, upslanted palpebral fissures, and prominent eyebrows. Three patients had seizures, including myoclonic, tonic-clonic, and febrile. Brain MRI showed variable changes, including enlarged ventricles, abnormal corpus callosum, and frontoparietal atrophy, but none had periventricular heterotopia. Another unrelated child with a point mutation in the MEF2C gene (S228X; 600662.0001) had a similar disorder, with delayed motor development, mental retardation, poor eye contact, absent speech, stereotypic movements, and seizures. Brain MRI in this patient showed enlarged ventricles and periventricular white matter hyperintensities.

Novara et al. (2010) reported 2 unrelated boys with severe mental retardation, seizures, hypotonia, lack of speech development, and variable dysmorphic features who carried different heterozygous deletions of chromosome 5q14 involving the MEF2C gene. Both presented in infancy with global psychomotor delay, poor visual contact, and hypotonia. Both had refractory myoclonic seizures, which progressed to refractory infantile spasms in 1. Brain MRI of 1 showed periventricular leukomalacia and frontal lobe atrophy, whereas imaging of the other patient showed ventricular dilatation and hypoplasia of the corpus callosum. Speech was absent in both patients, and 1 showed behavioral stereotypies. One patient had more significant dysmorphic features than the other, including plagiocephaly, hypertelorism, flattened nasal bridge, small and hooked nose, and low-set, dysmorphic ears.

Zweier et al. (2010) reported 4 unrelated patients with mental retardation due to heterozygous mutations in the MEF2C gene (see, e.g., 600662.0002-600662.0004). The patients had severe mental retardation with absence of speech and limited ability to walk, infantile-onset seizures, hypotonia, and variable subtle brain anomalies on imaging, such as enlarged ventricles and decreased myelination. Dysmorphic features included broad forehead, large ears with prominent ear lobes, mild upslanting palpebral fissures, and bowed or tented upper lip. Two additional patients with a similar phenotype had deletions involving the MEF2C gene.

Bienvenu et al. (2013) reported an 8-year-old girl with severe mental retardation who carried a de novo heterozygous mutation in the MEF2C gene (600662.0005). In infancy, she had poor feeding due to marked hypotonia and poor eye contact due to strabismus. Motor milestones were delayed, and she walked at age 4 years. At age 18 months, she had a single episode of myoclonic febrile seizures that were easily controlled. At age 7 years, she had poor growth, microcephaly (-2.5 SD), lack of speech, stereotypic movements, unstable wide-based gait, and happy demeanor. There were mild dysmorphic features, including large eyebrows, open mouth with thick everted lower lip, and anteverted nares. Brain MRI was normal.

Carvill et al. (2013) reported 2 unrelated patients with mental retardation and epileptic encephalopathy associated with de novo heterozygous mutations in the MEF2C gene. The patients had onset at 4 and 13 months, respectively, of multiple seizure types, including febrile seizures, hemiclonic seizures, absence seizures, tonic-clonic seizures, absence seizures, and myoclonic jerks. Both had EEG abnormalities, and 1 showed cognitive regression and autism spectrum disorder. The patients were ascertained from a large cohort of 500 patients with epileptic encephalopathy who underwent targeted sequencing of candidate genes.

Cytogenetics

Sobreira et al. (2009) identified a 7.4-Mb deletion on chromosome 5q14.3-q21 (chr5:90,787,099-98,232,469, NCBI36) in an 11-year-old boy with intellectual disability, bilateral iris coloboma, hearing loss, dental anomaly, and dysmorphic facial features, but without periventricular heterotopia. Sobreira et al. (2009) referred to the report by Cardoso et al. (2009), who identified deletions of chromosome 5q14 in patients with periventricular heterotopia (PVNH5; 612881). One of those patients had a unilateral coloboma and shared part of the deletion with the patient reported by Sobreira et al. (2009). Comparison of the shared deleted regions between the 2 patients delineated a putative 2.6-Mb region for coloboma (95,538,699-98,232,465 bp) and a putative 1.84-Mb region for periventricular heterotopia (88,945,075-90,787,099 bp).

Engels et al. (2009) reported 3 unrelated patients with severe psychomotor retardation, seizures, and hypotonia associated with de novo interstitial deletions of chromosome 5q14.3-q15. The 3 deletions were different, measuring 5.7, 3.9, and 3.6 Mb, respectively, but were overlapping. The 1.6-Mb common region contained 5 genes, including CETN3 (602907) and GPR98 (602851); GPR98 is known to be involved in epilepsy. Two of the deletions contained the MEF2C gene, whereas the third did not. Two patients had myoclonic seizures and the third had absence-like seizures. Other features included dysmorphic facies and variable brain anomalies, such as enlarged ventricles, aplasia of the cerebellar vermis and posterior corpus callosum, or white matter abnormalities. One of the patients had concentric myocardial hypertrophy, and another had stereotypic hand movements.

In 5 unrelated children with severe mental retardation, stereotypic movements, epilepsy, and cerebral malformations, Le Meur et al. (2010) identified 5 different interstitial de novo deletions of chromosome 5q14 ranging in size from 216 kb to 8.8 Mb. The minimal common deleted region contained only the MEF2C gene. Le Meur et al. (2010) noted that the chromosome 5q14 region partially overlapped with that deleted in patients with periventricular heterotopia reported by Cardoso et al. (2009), but that only 1 of those patients had deletion of the MEF2C gene. Moreover, none of the patients reported by Le Meur et al. (2010) had periventricular heterotopia.

Array analysis of the 2 patients reported by Novara et al. (2010) showed 2 different deletions of 5q14. One had a 318-kb deletion involving only the MEF2C gene, whereas the other had a larger 1.1-Mb deletion encompassing the MEF2C and TMEM161B genes. None of the breakpoints was similar and none occurred in low copy repeat regions. One deletion was proven to be de novo.

Molecular Genetics

In a child with mental retardation, delayed motor development, poor eye contact, absent speech, stereotypic movements, seizures, and brain MRI abnormalities, Le Meur et al. (2010) identified a de novo heterozygous mutation in the MEF2C gene (S228X; 600662.0001).

Zweier et al. (2010) identified 4 different de novo heterozygous mutations in the MEF2C gene (see. e.g., 600662.0002-600662.0004) in 4 (1.1%) of 362 probands with mental retardation who were screened for mutations in this gene. Two of the mutations were missense and 2 were truncating. Two additional patients with a similar disorder had heterozygous deletions (2.4- and 1.5-Mb, respectively) involving the MEF2C gene. Analysis of blood-derived RNA showed significantly decreased levels of MEF2C isoform-2 mRNA in all patients with deletions in the MEF2C region, including the patients reported by Engels et al. (2009), Cardoso et al. (2009), and Le Meur et al. (2010), suggesting haploinsufficiency as the disease mechanism. Decreased MEF2C levels were also found in the patient reported by Engels et al. (2009) whose deletion did not directly affect the MEF2C gene, consistent with a regulatory positional effect. The 2 patients with missense mutations did not show decreased MEF2C mRNA levels. All deletions and mutations caused significantly decreased MEF2C transcriptional activity, which could be rescued by wildtype MEF2C. The MEF2C gene was demonstrated to activate promoters of the MECP2 (300005) and CDKL5 (300203) genes. Finally, all patients, including the 2 with missense mutations, showed decreased levels of MECP2 mRNA, and all except 2 patients had decreased levels of CDKL5 mRNA. These 2 genes are involved in Rett or Rett syndrome-like phenotypes (312750 and 300672, respectively), which share some features with MRD20. Zweier et al. (2010) concluded that the phenotype results from involvement of a common pathway involving these 3 genes.