Mental Retardation, Autosomal Dominant 22

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-22 (MRD22) is caused by heterozygous mutation in the ZBTB18 gene (608433) on chromosome 1q44.

Description

MRD22 is characterized by impaired intellectual development with frequent cooccurrence of corpus callosum anomalies, hypotonia, microcephaly, growth problems, and variable facial dysmorphism (summary by van der Schoot et al., 2018).

Chromosome 1q43-q44 deletion syndrome is characterized by moderate to severe mental retardation, limited or no speech, and variable but characteristic facial features, including round face, prominent forehead, flat nasal bridge, hypertelorism, epicanthal folds, and low-set ears. Other features may include hypotonia, poor growth, microcephaly, agenesis of the corpus callosum, and seizures. The phenotype is variable, and not all features are observed in all patients, which may be explained in some cases by incomplete penetrance or variable expressivity (summary by Ballif et al., 2012).

Clinical Features

Johnson et al. (1985) reported a female infant with microcephaly, delayed psychomotor development, hypotonia, failure to thrive, and dysmorphic facies associated with a deletion of chromosome 1q42-qter. A review of 14 additional cases revealed a characteristic facial appearance including round face with prominent 'cupid's bow' and downturned corners of the mouth, thin vermilion borders of lips, long upper lip with smooth philtrum, short and broad nose, epicanthal folds, low-set ears, and micrognathia. Other features included microcephaly, growth retardation, and moderate to severe mental retardation. The deletion included 1q42 or 1q43-qter and was a de novo defect in 9 of 15 cases.

De Vries et al. (2001) reported a boy with mental retardation and a submicroscopic distal deletion of chromosome 1q. He had delayed visual use, seizures, short stature, microcephaly, partial agenesis of the corpus callosum, and lack of speech development. Dysmorphic features included full round face, short broad nose with a broad base and flat nasal bridge, long smooth philtrum with a thin vermilion border, and prominent ears.

Van Bon et al. (2008) reported 11 unrelated patients with a submicroscopic deletion of chromosome 1q43-q44. Common clinical features included severe mental retardation with serious speech impairment, hypotonia, and motor delay. Some patients were able to walk eventually. Many patients had a low birth weight, microcephaly, short stature, seizures, and feeding problems. Common dysmorphic features included round face, deep-set eyes, prominent metopic ridge, short nose with a broad or prominent nasal tip, thin bow-shaped upper lip, and widely spaced teeth. However, in contrast to previous reports, low-set ears, hypertelorism, epicanthic folds, long philtrum, cleft palate, and microretrognathia were not frequently noted. Nine patients showed corpus callosum abnormalities, all of whom shared a common 360-kb overlapping region in 1q44; the AKT3 gene (611223) was not within the critical region. Two additional sibs with a 1q43-q44 deletion were reported, but the deletion was also present in their unaffected mother, and the clinical phenotypes were not compatible with the 1qter deletion phenotype.

De Munnik et al. (2014) reported a 34-month-old girl, conceived by in vitro fertilization, with global developmental delay, severely delayed speech, short stature, poor growth, and microcephaly. Dysmorphic facial features included arched eyebrows with telecanthus, short palpebral fissures, long nose with prominent tip, short philtrum, thin upper lip, and micrognathia. Absence seizures were suspected; brain MRI was normal.

Lopes et al. (2016) reported a girl with severe intellectual disability, absent speech, and microcephaly. She presented in early infancy with delayed motor development and showed signs of regression at age 8 months, consistent with delayed psychomotor development. She also had hand stereotypies, intense eye communication, breathing disturbances, and screaming spells, suggesting a diagnosis of atypical Rett syndrome (RTT; 312750), but sequencing of the MECP2 (300005) gene revealed no mutations. The patient also showed bruxism and dystonia; brain MRI was normal.

Cohen et al. (2017) identified 5 unrelated patients with MRD22 ascertained from several research centers that performed exome sequencing. All had developmental delay and intellectual disability, although there was a wide range of severity. The most severely affected patient had profound intellectual disability, learned to walk with a walker at age 6 years, and had no spoken words. He had additional features, such as bifid uvula, widely-spaced nipples, cryptorchidism, and truncal hypotonia with spasticity of the lower limbs. The other patients had variably delayed psychomotor development with poor or absent speech; 1 had normal motor development. Some had mild dysmorphic features without a clear common pattern. One patient had microcephaly and another had seizures with multifocal spikes and sharp waves on electroencephalogram (EEG). Brain imaging of all 4 patients who were imaged showed hypoplasia of the corpus callosum, to varying degrees.

Van der Schoot et al. (2018) reported 4 unrelated patients with MRD22 and summarized clinical information on 21 previously reported patients. All 25 patients had developmental delay, but the remaining features were more variable, including 7 of 17 with microcephaly, 9 of 15 with corpus callosum abnormalities, 10 of 13 with dysmorphic facial features, and 4 of 17 with seizures. The authors concluded that pathogenic variants in ZBTB18 have an extensive and highly variable phenotypic impact.

Cytogenetics

Boland et al. (2007) described detailed mapping studies of patients with unbalanced structural rearrangements of distal 1q4. These defined a 3.5-Mb critical region that was hypothesized to contain one or more genes that lead to agenesis of the corpus callosum and microcephaly when present in only 1 functional copy. Mapping of a balanced reciprocal t(1;13)(q44;q32) translocation in a patient with postnatal microcephaly and agenesis of the corpus callosum demonstrated a breakpoint in this region that was situated 20 kb upstream of AKT3, a serine-threonine kinase. The murine ortholog Akt3 is required for developmental regulation of normal brain size and callosal development. Whereas sequencing of AKT3 in a panel of 45 patients with agenesis of the corpus callosum did not demonstrate any pathogenic variations, whole-mount in situ hybridization confirmed expression of AKT3 in the developing central nervous system during mouse embryogenesis. Boland et al. (2007) concluded that thus, AKT3 represents an excellent candidate for developmental human microcephaly and agenesis of the corpus callosum, and suggested that haploinsufficiency causes postnatal microcephaly and agenesis of the corpus callosum.

Ballif et al. (2012) reported 22 unrelated patients with interstitial or terminal deletions involving chromosome 1q43-q44 identified by microarray analysis. The deletions ranged in size from 120 kb to 6.0 Mb. All had different breakpoints, and many of them did not overlap. The phenotype was similar, but variable. Thirteen patients had microcephaly, and all but 1 of these patients had a deletion spanning or interrupting the AKT3 gene. One patient inherited a deletion within the AKT3 gene from his mother, who also had microcephaly. Seven of the 22 patients had abnormalities of the corpus callosum, 6 of whom had deletions affecting the ZNF238 gene (608433); however, 3 patients with deletions affecting this gene had normal brain MRI. Nine patients had a seizure disorder, with the smallest common region of deletion including the FAM36A (COX20; 614698), C1ORF199, and HNRNPU (602869) genes. However, 2 patients without seizures also had deletions spanning this region. Combining the data from this and 5 previously published studies of 1q43-q44 deletions indicated that the proposed model of Ballif et al. (2012) for involvement of critical regions for specific features fit for 42 (93%) of 45 cases with microcephaly; 37 (86%) of 43 cases with agenesis of the corpus callosum; and 40 (87%) of 46 cases with seizures.

Molecular Genetics

In a girl with autosomal dominant mental retardation-22, de Munnik et al. (2014) identified a de novo heterozygous nonsense mutation in the ZBTB18 gene (E133X; 608433.0001). The mutation was found by exome sequencing and confirmed by Sanger sequencing. No additional mutations in the ZBTB18 gene were found in 9 patients with a similar phenotype, and no stop or truncating mutations in this gene were found in the Exome Variant Server database. The patient's features were similar to those found in patients with the chromosome 1q43-q44 deletion syndrome.

In a girl with MRD22, Lopes et al. (2016) identified a de novo heterozygous nonsense mutation in the ZBTB18 gene (R186X; 608433.0002). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.

In 5 unrelated patients with MRD22, Cohen et al. (2017) identified 5 different de novo heterozygous mutations in the ZBTB18 gene (see, e.g., 608433.0003-608433.0006). There were 2 missense and 3 truncating mutations. The mutations were found by whole-exome sequencing among several research centers. Functional studies of the variants and studies of patient cells were not performed, but Cohen et al. (2017) postulated haploinsufficiency as the pathogenic mechanism. However, the authors noted that the 2 patients with missense mutations had a more severe phenotype than those with truncating mutations, suggesting the possibility of a dominant-negative effect.

Among 4 unrelated patients with MRD22, van der Schoot et al. (2018) identified 4 different de novo heterozygous mutations in the ZBTB18 gene, including a nonsense, a frameshift, and 2 missense mutations. Three of the variants were identified using whole-genome sequencing and the fourth was identified through the GeneMatcher exchange. One of the missense mutations (608433.0007) had previously been reported in 3 patients with MRD22 (Cohen et al., 2017; Depienne et al., 2017). Based on a review of the 25 reported patients with MRD22 and ZBTB18 mutations, including their own, van der Schoot et al. (2018) found no genotype-phenotype correlations.

Animal Model

Mice with loss of Zbtb18 die at birth with neocortical defects. Xiang et al. (2012) found that conditional knockout of the gene in the central nervous system resulted in microcephaly, reduced thickness of the cortex, agenesis of the corpus callosum, and cerebellar hypoplasia. Examination of the cortex showed defective organization of the layers, with a loss of some layer-specific neurons and widespread deficits in neuronal positioning during cortical plate formation. Znf238-mutant brains maintained neuronal precursor pools, but had decreased neuronal and increased glial differentiation. Chromatin immunoprecipitation (ChIP) analysis showed that Zbtb18 repressed the proneurogenic genes Ngn2 (606624) and Neurod1 (601724) in intermediate neurogenic progenitor cells by binding to promoter regions in these genes. Xiang et al. (2012) concluded that Zbtb18 favors neuronal differentiation and brain growth by repressing multiple proneurogenic genes in a timely manner, and thus plays a major role in the promotion of ordered neurogenesis leading to proper layer formation and cortical growth. The phenotype in the mutant mice resembled that seen in patients with chromosome 1q43-q44 deletion syndrome.