Mental Retardation, Autosomal Dominant 1
A number sign (#) is used with this entry because this form of mental retardation (MRD1) can be caused by heterozygous mutation in or disruption of the MBD5 gene (611472) on chromosome 2q23.1.
Clinical FeaturesChromosome 2q23.1 Deletion Syndrome
Wagenstaller et al. (2007) described a boy with severe mental retardation who additionally had a sandal gap between the first and second toe, but no facial dysmorphic features. He showed retarded motor development and had febrile seizures at age 8 months and seizures without fever starting at age 16 months. The boy was hypoactive, and social interactions were limited.
Jaillard et al. (2009) reported 2 unrelated 10-year-old boys, both born to nonconsanguineous French parents, with 2q23.1 microdeletion. Both boys had severe psychomotor retardation and language impairment, microcephaly, seizures, and ataxia.
Van Bon et al. (2010) reported 11 unrelated patients with 2q23.1 deletions, including 9 patients reported for the first time. One of the patients had a similarly affected sib. All were mentally retarded with pronounced speech delay. Additional abnormalities included short stature, seizures, microcephaly, and coarse facies with broad forehead and everted lower lip. The majority of cases presented with stereotypic repetitive behavior, a disturbed sleep pattern, and a broad-based ataxic gait. Less common features included hyperphagia, short hands, and short fifth digits. These features led to the initial clinical impression of Angelman syndrome (105830), Rett syndrome (RTT; 312750), or Smith-Magenis syndrome (SMS; 182290) in several patients.
Williams et al. (2010) reported 2 additional unrelated patients with chromosome 2q23.1 deletion syndrome. The patients had severe developmental and cognitive delay, minimal speech, infantile hypotonia, seizures, microcephaly, mild craniofacial dysmorphism such as wide mouth and tented upper lip, behavioral disorders, and short stature.
From a large international multicenter collaboration, Talkowski et al. (2011) ascertained 65 patients with heterozygous deletion (63 cases) or translocation (2 cases) involving the MBD5 gene. An analysis of 48 phenotypic features showed that most (81.2%) of the features of 2q23.1 deletion syndrome were consistent between both MBD5-specific alterations and larger deletions. All patients had developmental delay, motor delay, seizures, language impairment, and various behavioral problems, including short attention span, self-injurious behavior, aggression, and autistic-like features. Common craniofacial anomalies included thick or arched eyebrows, thin upper lip, widely spaced teeth, and small chin. Eye abnormalities included esotropia, myopia, astigmatism, hypermetropia, and poor vision, and nasal abnormalities included large prominent nose in older individuals and small bulbous nose in younger individuals.
Mullegama et al. (2015) reviewed 74 cases with either MBD5-specific deletions or 2q23.1 deletions, published either as case reports or series. Developmental delay and motor delay were present in 100% of those assessed, while seizures were seen in 85% and severe language impairment in 94%. Infantile hypotonia and feeding difficulties were present in more than 85% assessed while autistic-like behavioral problems were reported in 98%. Attention span difficulties were present in 100%, and sleep disturbances in 79%. Close to 70% had short stature; craniofacial abnormalities included microcephaly in 61%, broad forehead in 70%, and arched/thick eyebrows in 79%.
Chromosome 2q23.1 Duplication Syndrome
Chung et al. (2012) reported 2 patients with developmental delay, hypotonia, and autistic features who had duplications of chromosome region 2q23.1-q23.2. Patient 1, a girl, was born at term to healthy nonconsanguineous parents. The father was of Scottish descent and the mother of African-Caribbean and British descent. Birth weight was at the third percentile, and the patient was hospitalized for 2 weeks with poor feeding and hypotonia. Outer canthal and interpupillary distances were increased, but inner canthal distance was normal. The remainder of the physical examination was unremarkable except for hypotonia. She walked independently at 18 months of age and said her first word at age 2 years. She was diagnosed with global developmental delay at age 4 years. She was diagnosed with autism at age 8 and had a total vocabulary of 20 words. At age 17, examination showed head circumference at the 25 percentile, low anterior hairline, arched eyebrows with lateral ptosis, and bulbous nasal tip. Aggressive behavior was present. Hearing and vision were normal, and she did not have seizures. Patient 2 was an 8-year-old male of nonconsanguineous Caucasian descent referred for genetic evaluation because of developmental delay and autistic features. He had shown poor neonatal feeding, hypotonia, and in the first year of life had experienced gastroesophageal reflux and recurrent vomiting. He had global developmental delay and was unable to walk or talk until the age of 2 years. At age 8 years he performed at the kindergarten level for reading and writing. All growth parameters were above the 98th percentile at 8 years of age. He had subtle facial asymmetry, right hemifacial microsomia, strabismus, high-arched palate, and dental crowding. His nose was long and tubular with a prominent tip, and he had bilateral fifth finger clinodactyly. Seizures were not present.
Autosomal Dominant Mental Retardation 1
Carvill et al. (2013) reported a 20-year-old woman with severe mental retardation and autism spectrum disorder associated with epileptic encephalopathy who had a de novo heterozygous mutation in the MBD5 gene (611472.0002). In infancy, she had delayed development and onset of tonic-clonic seizures at age 6 months. She later developed absence seizures, focal dyscognitive seizures, focal seizures, and tonic seizures associated with multiple EEG abnormalities. The report expanded the phenotype associated with MBD5 mutations.
InheritanceAmong 11 patients with chromosome 2q23.1 deletion syndrome, van Bon et al. (2010) found that all with available parent samples had a de novo deletion. In 1 family, the presence of the same deletion in 2 affected sibs suggested parental gonadal mosaicism.
CytogeneticsChromosome 2q23.1 Deletion Syndrome
In 2 unrelated 10-year-old boys with 2q23.1 deletion, Jaillard et al. (2009) identified an overlapping region of 250 kb that included 2 genes: MBD5 and EPC2 (611000).
In a review of 15 patients with chromosome 2q23.1 deletion syndrome, van Bon et al. (2010) found that the deletion sizes ranged from 250 kb to 5.5 Mb comprising 15 genes. All patients except the sib pairs, had a deletion of at least the MBD5 and EPC2 genes, but the overlapping region contained only MBD5.
Two patients reported by Williams et al. (2010) had 930-kb and 3.51-Mb deletions at chromosome 2q23.1, respectively. RT-PCR of patient lymphoblasts or lymphocytes showed an approximately 50% reduced expression of the MBD5 and EPC2 genes compared to controls.
From a large international multicenter collaboration, Talkowski et al. (2011) ascertained 65 patients with heterozygous deletion (63 cases) or translocation (2 cases) involving chromosome 2q23.1. The deletions ranged in size from 38 kb to greater than 19 Mb. The smallest region of overlap in all cases was confined to 1 gene, MBD5, and 14 (21.5%) of the 65 microdeletions and translocations were exclusively localized to MBD5, including several deletions that were restricted to noncoding regions and did not alter the protein sequence. The deletions or translocations were associated with haploinsufficiency of the MBD5 gene (22.5 to 55.4% of controls), as determined by mRNA expression analysis.
Chromosome 2q23.1 Duplication Syndrome
The 2 patients described by Chung et al. (2012) with developmental delay, hypotonia, and autistic features carried overlapping microduplications of chromosome 2q23.1-q23.2 involving 8 genes, including MBD5 (611472) and EPC2 (611000). The duplication in patient 1 was estimated to be 1.64 Mb and was represented by oligonucleotide probes from positions chr2:148,691,798-chr2:150,343,042 (NCBI37/hg19). The approximately 2-Mb duplication in patient 2 had a maximum interval of chr2:148,186,210-150,188,492 and a minimum interval of chr2:148,616,673-150,420,742 (NCBI37/hg19). The duplication in patient 2 was demonstrated to be a de novo occurrence. Real-time qRT-PCR of lymphocytes from patient 1 showed overexpression of MBD5 and EPC2.
Molecular GeneticsIn the patient described by Wagenstaller et al. (2007) with severe mental retardation and seizures, the authors found a 200-kb deletion in the MBD5 gene (611472.0001). The deletion region was present in parental DNA. They authors also identified 4 missense variants in MBD5 among 415 DNAs from children with mental retardation that were not present in 660 controls.
Talkowski et al. (2011) identified MBD5 deletions in approximately 0.18% of patients with autism from 2 large cohorts (1,786 and 2,275 patients, respectively), whereas deletions at this locus were not found in 7,878 controls. Moreover, there was a significant association between a gly79-to-glu (G79E) missense variant in a highly conserved methyl-CpG-binding domain in 747 patients with autism spectrum disorder compared with 2,043 controls (odds ratio of 5.47, p = 0.012). The results suggested that alterations of MBD5 predispose to the risk of autism spectrum disorders. Talkowski et al. (2011) noted that the MBD5 gene belongs to a family of genes involved in DNA methylation and/or chromatin remodeling, like MECP2 (300005), which is mutant or deleted in Rett syndrome (RTT; 312750), intellectual disabilities, and autism, providing further evidence that alterations of MBD5 may predispose to the risk of these neurodevelopmental disorders.
Carvill et al. (2013) identified a de novo heterozygous truncating mutation in the MBD5 gene (611472.0002) in a 20-year-old woman with severe mental retardation and epileptic encephalopathy.
In a patient with some features of Kleefstra syndrome (610253), Kleefstra et al. (2012) detected a frameshift mutation in the MBD5 gene (611472.0003). The patient was 1 of 9 patients with syndromic mental retardation who shared core features of Kleefstra syndrome but were phenotypically heterogeneous otherwise, with a phenotype referred to by the authors as Kleefstra syndrome spectrum (KSS) .
Genotype/Phenotype CorrelationsIn a phenotypic comparison of 14 patients with deletions of chromosome 2q23.1 limited to the MBD5 gene and 51 patients with larger deletions of this region and involving other genes, Talkowski et al. (2011) found that those with larger deletions tended to have more severe craniofacial dysmorphisms, including microcephaly, external ear abnormalities, wide mouth, open mouth, and downturned corners of the mouth. Those with larger deletions also had a higher frequency of ataxia, hyperphagia, postnatal growth retardation, and small hands and feet. These additional features were attributed to the involvement of other deleted genes.
HistoryIn 2 families with undifferentiated mental retardation occurring in members of multiple generations, Dekaban and Klein (1968) concluded that dominant transmission (i.e., a single major gene) could be responsible.