Chromosome Xp11.22 Duplication Syndrome

A number sign (#) is used with this entry because of evidence that the phenotype is caused by microduplications within a region of chromosome Xp11.22 (chrX:53.0-54.3 Mb) that involve the HSD17B10 (300256) and HUWE1 (300697) genes. Increased dosage of HUWE1 is believed to be responsible for the phenotype (Froyen et al., 2012).

Point mutations in the HSD17B10 and HUWE1 genes have been found to cause syndromic forms of mental retardation, MRXS10 (see 300438) and MRXST (309590), respectively.

Clinical Features

Gedeon et al. (1994) reported a family in which 6 males spanning 3 generations had moderate mental retardation with slow speech development inherited in an X-linked pattern. No significant common dysmorphic features were noted.

Donnelly et al. (1996) reported a 4-generation family with multiple males affected with global retardation that became apparent between ages 2 and 4 years. Inheritance was X-linked. Affected males had moderate mental retardation without other obvious abnormalities.

Froyen et al. (2008) reported 4 families with X-linked mental retardation. Affected individuals in 1 of the families, of Finnish origin, had moderate mental retardation, speech difficulties, dysarthria, and mild dysmorphic facies. Affected individuals in the other families showed mild to moderate intellectual handicap with speech delay and hyperactivity. One patient had moderate macroorchidism.

Mapping

By linkage analysis of a family with X-linked mental retardation, Gedeon et al. (1994) found linkage to the AR (313700) locus on chromosome Xq11-q12 (maximum lod score of 2.40). Gedeon et al. (1994) termed the locus MRX17.

By linkage analysis of a family with X-linked mental retardation, Donnelly et al. (1996) identified a locus, termed MRX31, within a 12-cM pericentromeric region between Xp11.23 (DXS1126) and Xq13.3 (DXS1124). The highest lod score was 3.44 at the AR locus.

Cytogenetics

Using X chromosome-specific array comparative genomic hybridization (array CGH), Froyen et al. (2008) identified overlapping microduplications of chromosome Xp11.22 in affected individuals from 6 unrelated families with nonsyndromic X-linked mental retardation, including the 2 families reported by Gedeon et al. (1994) and Donnelly et al. (1996). Subsequent PCR analysis showed that the duplicated regions varied from 0.4 to 0.8 Mb with a common minimal overlapping region that contained 2 candidate genes, HSD17B10 and HUWE1, both of which showed 2- to 5-fold overexpression in blood cells from affected individuals.

Froyen et al. (2012) reported 6 additional families with nonsyndromic X-linked mental retardation associated with duplications at Xp11.22. All patients had mild to moderate intellectual disability, but some were able to attend school. Most patients had some additional variable features, but these features were not consistent enough to form a discernible pattern. These variable features included facial dysmorphism, urogenital anomalies, gastroesophageal reflux, and abnormal gait. Some had EEG abnormalities and some had behavioral problems. All female carriers were phenotypically normal. One of the families had previously been reported by Madrigal et al. (2007). Microarray analysis identified 6 different but overlapping duplications of chromosome Xp11.22 ranging in size from 0.4 to 1.0 Mb that segregated with the phenotype. Combined with the cytogenetic data from the 6 families reported by Froyen et al. (2008), Froyen et al. (2012) found that the common minimal region of overlap is 228 kb, which contains the HUWE1 gene and excludes the HSD17B10 gene. Cell lines from patients showed 2-fold increased expression of HUWE1, and studies in 4 female carriers showed skewed X inactivation. The authors concluded that HUWE1 is the dosage-sensitive gene for which a 2-fold overexpression results in cognitive impairment in males. All proximal and distal breakpoints differed, excluding nonallelic homologous recombination (NAHR) as the common mechanism. Junction and in silico analysis of breakpoint regions showed that some contained repetitive sequences, palindromes, increased GC content, or microhomology-mediated rearrangements suggestive of replication-based duplication events. The duplication was shown to be due to NAHR in only 1 family, whereas it was due to other mechanisms in the other families; however, many breakpoints could not adequately be studied. The findings indicated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.