Four unrelated patients with lubs X‐linked mental retardation syndrome and different Xq28 duplications

Abstract

The Lubs X-linked mental retardation syndrome (MRXSL) is caused by small interstitial duplications at distal Xq28 including the MECP2 gene. Here we report on four novel male patients with MRXSL and different Xq28 duplications delineated by microarray-based chromosome analysis. All mothers were healthy carriers of the duplications. Consistent with an earlier report [Bauters et al. (2008); Genome Res 18: 847-858], the distal breakpoints of all four Xq28 duplications were located in regions containing low-copy repeats (LCRs; J, K, and L groups), which may facilitate chromosome breakage and reunion events. The proximal breakpoint regions did not contain known LCRs. Interestingly, we identified apparent recurrent breakage sites in the proximal and distal breakpoint regions. Two of the four patients displayed more complex rearrangements. Patient 2 was endowed with a quadruplicated segment and a small triplication within the duplication, whereas patient 3 displayed two triplicated segments within the duplication, supporting that the Fork Stalling and Template Switching (FoSTeS) model may explain a subset of the structural rearrangements in Xq28. Clinically, muscular hypertonia and contractures of large joints may present a major problem in children with MRXSL. Because injection of botulinum toxin (BT-A; Botox) proved to be extremely helpful for patient 1, we recommend consideration of Botox treatment in other patients with MRXSL and severe joint contractures.

Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans

“…The high prevalence of repetitive sequences at both breakpoint junctions, including many long-interspersed elements (LINES) at the 5′ region of MARS2 , and several AT-rich repeat sequences are likely to have mediated the rearrangements (Figure 7A) [67],[68]. Despite the increased mRNA levels, we observed decreased MARS2 protein levels.…”

Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation

“…abased on the compiled data of affected males summarized in [2] ( n  = 119) [5], ( n  = 6) [6], ( n  = 4) [7], ( n  = 1) [8], ( n  = 1) [9], ( n  = 3) [13], ( n  = 1), and [20] ( n  = 7).…”

De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation

“…In familial cases with X-linked pedigrees, the asymptomatic female carriers show a significant skewing of X-inactivation (XCI). [7][8][9] Besides mental retardation, the main features of the affected boys are muscular hypotonia, progressive spasticity, seizures, poor speech and recurrent infections. The reported duplications vary from 0.1 to 2.6 Mb with the minimal critical region containing the IRAK and MECP2 genes.…”

“…The reported duplications vary from 0.1 to 2.6 Mb with the minimal critical region containing the IRAK and MECP2 genes. 7 In familial cases, carrier females might suffer from endocrinological abnormalities, autoimmune diseases, as well as psychiatric disorders. 10 A phenotype with mental retardation has been reported only two times.…”