A number sign (#) is used with this entry because this disorder is caused by copy number increase of a small region on distal chromosome Xq28. One report has identified a 0.3-Mb region of Xq28 (chrX:153.2-153.5 Mb, NCBI36) containing at least 11 genes and including the GDI1 gene (300104), which is mutated in MRX41 (300849). Two additional reports have identified a more distal 0.5-Mb region (chrX:153.7-154.2 Mb (NCBI36/hg19)) containing at least 8 genes and including the RAB39B gene (300774), which is mutated in MRX72 (300271).

Vandewalle et al. (2009) reported 4 families with X-linked mental retardation. The first family was of Belgian origin and had 4 affected males in 2 generations. All had normal growth, moderate mental retardation, and variable mild dysmorphic features, including mild 2-3 toe syndactyly, ataxic gait, and strabismus. The second family was of German origin and consisted of 2 affected brothers. The older brother was of average gestational size but was very floppy and was found to have a classic Dandy-Walker malformation, with cerebellar hypoplasia and agenesis of the corpus callosum. He developed seizures at 15 months of age and was microcephalic. Dysmorphic features included large ears, upslanting palpebral fissures, epicanthal folds, and thin lips. His brother also had a Dandy-Walker malformation, with agenesis of the cerebellar vermis and hypoplasia of the corpus callosum. At 19 months he had not developed seizures but had microcephaly. The third family reported by Vandewalle et al. (2009) was of Spanish origin and was reported as case 6 by Madrigal et al. (2007). The index case was born to nonconsanguineous parents at 8 months of pregnancy complicated by an acute pancreatitis. He developed neonatal seizures and cyanotic crises, and was hospitalized for 10 days. Imaging of his brain showed ventricular dilatation and large asymmetric cisterna magna. Gross motor milestones were within normal range. His speech development was delayed. At age 7, he had mild dysmorphic features with microcephaly, a high palate, medial eyebrow flare, and prominent ears. His IQ was 58. Neurologic examination was normal. No clinical details were available for 2 maternal brothers who were institutionalized. The fourth family was a sporadic case born to healthy, unrelated German parents. He had mild global psychomotor delay and did not begin walking until 20 months of age. Mild dysmorphic features were present, including brachycephaly, broad forehead, hypotelorism, and epicanthus inversus, more pronounced at the left side. He had a rather flat midface with flat nasal root and a short philtrum. He had a high palate and a small chin. Head circumference was at the 25th percentile.

In addition to mental retardation and dysmorphic features, Vandewalle et al. (2009) found ventricular aberrations in 2 families. A large fourth ventricle was seen in family 1, and a ventricular dilatation in family 3.

El-Hattab et al. (2011) reported 4 boys, including 2 brothers, with intellectual disability and behavioral disorders associated with a recurrent approximately 0.5-Mb duplication of chromosome Xq28 identified through array CGH. The duplications spanned chrX:153.7-154.2 Mb (NCBI36/hg19), and were confirmed by FISH analysis. All 3 mothers, who were more mildly affected with learning difficulties, also carried the duplication. X-chromosome inactivation studies showed skewed patterns in all 3 of the mothers, 2 with preferential inactivation of the normal chromosome and 1 with preferential inactivation of the duplicated chromosome. DNA sequence analysis showed that the breakpoints occurred within the directly oriented low-copy repeat (LCR) regions int22h-1 and int22h-2, which are in or close to the F8 gene (300841). The duplicated region contained 9 genes, including RAB39B (300774), but not GDI1 (300104). All 4 boys with the duplication had cognitive impairment, aggressive and/or hyperactive behavior, recurrent ear infections or pneumonia, and mildly dysmorphic facial features, including high forehead, upper eyelid fullness, broad nasal bridge, and thick lower lip. A mother and daughter from a fourth family were found to carry a heterozygous reciprocal deletion of Xq28 with 100% skewed X-chromosome inactivation of the chromosome with the deletion. Neither had intellectual disability, but the daughter came to attention for hyperactivity, inattentiveness, and sensory integration difficulties. The mother had a history of 2 spontaneous abortions, which El-Hattab et al. (2011) postulated may indicate that the deletion is lethal to males in utero.

Vanmarsenille et al. (2014) reported 4 male patients, including 2 brothers, with intellectual disability associated with a recurrent approximately 0.5-Mb duplication at distal chromosome Xq28 (chrX: 154.1-154.6 (hg19)). The duplications were apparently the same as those reported by El-Hattab et al. (2011), and the breakpoints involved the int22h-1 and int22h-2 LCRs. The duplicated region was distal to and did not include the GDI1 gene. Cell lines from 2 of the patients showed increased mRNA expression of BRCC3 (300617), VBP1 (300133), and RAB39B. The patients had behavioral or psychiatric problems, including schizophrenia in 1, and variable dysmorphic features, such as high forehead, large ears, deep-set eyes, and thin upper lip. Vanmarsenille et al. (2014) noted that point mutations in the RAB39B gene can cause X-linked mental retardation-72 (MRX72; 300271). Overexpression of Rab39b in mouse primary hippocampal neurons resulted in a significant decrease in neuronal branching as well as a decrease in the number of synapses compared to controls. These findings led Vanmarsenille et al. (2014) to conclude that increased dosage of the RAB39B gene causes disturbed neuronal development leading to cognitive impairment.

In 4 families with X-linked mental retardation, Vandewalle et al. (2009) identified copy number gain of an identical 0.3-Mb region at chromosome Xq28 that included 18 annotated genes. Of these, RPL10 (312173), ATP6AP1 (300197), and GDI1 (300104) are expressed in brain. Vandewalle et al. (2009) considered GDI1 the most likely candidate gene in the region, as its copy number correlated perfectly with severity of clinical features and mutations in GDI1 have been found to cause mental retardation. Families 1 and 3 carried 3 copies of GDI1, family 2 carried 5, and family 4, 2. Vandewalle et al. (2009) noted that the duplicated region of chromosome Xq28 harbored by affected individuals did not contain the MECP2 gene (300005) and is thus distinct from the duplicated region associated with MECP2 duplication syndrome (300260). Clinical features also differ.

Fusco et al. (2010) commented on the paper by Vandewalle et al. (2009). They differed with the conclusion of Vandewalle et al. (2009) that increased GDI1 expression is likely to be responsible for the mental retardation seen in this duplication syndrome, and considered the IKBKG gene (300248), also in the interval, to be likely to play a role in the mental retardation associated with this duplication. Fusco et al. (2010) concluded that the presence of high repetitive DNA sequence families, low copy repeats (LCRs), and a nonprocessed pseudogene sequence in the Xq28 region can enhance homologous recombination, and that several studies had pointed out the ability of L1 and L2 copies to recombine giving rise to both pathologic and nonpathologic structural variants. The recombinant alleles reported by Vandewalle et al. (2009) fit very well with these previous findings. In addition, Fusco et al. (2010) wondered whether any other gene in the duplicated region may play a role in the mental retardation phenotype described by the authors and, in particular, favored the analysis of IKBKG because it is located exactly in the recombination region, and because studies had suggested that any upregulation or decreased expression may cause cellular dysfunction, and thus disease, in a tissue (brain)-specific manner. Froyen (2010) replied to Fusco et al. (2010) on behalf of Vandewalle et al. (2009).