Dosage-Dependent Severity of the Phenotype in Patients with Mental Retardation Due to a Recurrent Copy-Number Gain at Xq28 Mediated by an Unusual Recombination

Abstract

We report on the identification of a 0.3 Mb inherited recurrent but variable copy-number gain at Xq28 in affected males of four unrelated families with X-linked mental retardation (MR). All aberrations segregate with the disease in the families, and the carrier mothers show nonrandom X chromosome inactivation. Tiling Xq28-region-specific oligo array revealed that all aberrations start at the beginning of the low copy repeat LCR-K1, at position 153.20 Mb, and end just distal to LCR-L2, at 153.54 Mb. The copy-number gain always includes 18 annotated genes, of which RPL10, ATP6AP1 and GDI1 are highly expressed in brain. From these, GDI1 is the most likely candidate gene. Its copy number correlates with the severity of clinical features, because it is duplicated in one family with nonsyndromic moderate MR, is triplicated in males from two families with mild MR and additional features, and is present in five copies in a fourth family with a severe syndromic form of MR. Moreover, expression analysis revealed copy-number-dependent increased mRNA levels in affected patients compared to control individuals. Interestingly, analysis of the breakpoint regions suggests a recombination mechanism that involves two adjacent but different sets of low copy repeats. Taken together, our data strongly suggest that an increased expression of GDI1 results in impaired cognition in a dosage-dependent manner. Moreover, these data also imply that a copy-number gain of an individual gene present in the larger genomic aberration that leads to the severe MECP2 duplication syndrome can of itself result in a clinical phenotype as well.

NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications

“…X-chromosome array-CGH identified a small Xq28 microduplication in patient HT previously reported in the paper by Bauters et al 13 Patient 5 was reported previously as patient IV:2 from family 1 by Vandewalle et al 14 Briefly, this patient presented with delayed psychomotor development, tiptoeing and mild atactic gait. Cognitive evaluation showed a moderate ID, with a total IQ of 50.…”

“…14 The aneusomic chromosomic fragment includes 18 annotated genes including IKBKG. MRI showed white matter abnormal hyperintense signals on both FLAIR and T2-weighted sequences and thin corpus callosum.…”

The Chromatin Regulator Brpf1 Regulates Embryo Development and Cell Proliferation

“…Rpl10l is highly homologous to Rpl10 (61), so we can speculate about Rpl10l functions from various studies of Rpl10, known to be important for nuclear export and allosteric movement of the 60 S ribosomal subunit (62,63). Human RPL10 mutations have been detected in leukemia (64,65) and implicated in abnormal brain development leading to autism (66), intellectual disability (67,68), and microcephaly (69). Moreover, faulty translation resulting from loss of other ribosomal proteins constitutes an important pathogenic mechanism (69,70) and causes diverse developmental defects (71)(72)(73).…”

Clinical and genetic heterogeneity in hereditary spastic paraplegias: From SPG1 to SPG72 and still counting

“…Cognitive impairment in SPG11 HSP is usually noticed in childhood and progresses insidiously to severe functional disability of a frontal type over a period of 10-20 years 133 . An age at onset in early childhood and/or delayed psychomotor development exists in some individuals 134 In addition, recurrent duplications or triplications of a region comprising 16 genes (including RPL10, ATP6AP1 and GDI1) on chromosome Xq28 have been shown to cause HSP and ID whose severity is dependent on the copy number 136 . More generally, the association of HSP and ID is an indication to search for genomic rearrangements using microarrays.…”