Molecular karyotyping of patients with unexplained mental retardation by SNP arrays: A multicenter study

McMullan, Dominic; Bonin, Michael; Hehir‐Kwa, Jayne Y.; Vries, Bert B.A. de; Dufke, Andreas; Rattenberry, Eleanor; Steehouwer, Marloes; Moruz, Luminita; Pfundt, Rolph; Leeuw, Nicole de; Rieß, Angelika; Altug‐Teber, Özge; Enders, Herbert; Singer, Sylke; Grasshoff, Ute; Walter, Michael; Walker, J. M.; Lamb, Catherine V.; Davison, E. V.; Brueton, Louise; Rieß, Olaf; Veltman, Joris A.

doi:10.1002/humu.21015

Cited by 66 publications

(46 citation statements)

References 42 publications

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“…These should have shown MECP2 duplications in females, and yet no further affected girls have been reported. 16 This contradicts the investigation bias as an explanation for the rarity of those cases. We conclude that MECP2 duplications are a comparatively rare cause of mental retardation in females.…”

Section: Discussionmentioning

confidence: 90%

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

et al. 2011

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Xq28 duplications including MECP2 are a well-known cause of severe mental retardation in males with seizures, muscular hypotonia, progressive spasticity, poor speech and recurrent infections that often lead to early death. Female carriers usually show a normal intellectual performance due to skewed X-inactivation (XCI). We report on two female patients with a de novo MECP2 duplication associated with moderate mental retardation. In both patients, the de novo duplication occurred on the paternal allele, and both patients show a random XCI, which can be assumed as the triggering factor for the phenotype. Furthermore, we describe the phenotype that might be restricted to unspecific mild-to -moderate mental retardation with neurological features in early adulthood.

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Section: Discussionmentioning

confidence: 90%

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

et al. 2011

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“…Copy numbers were determined using the 2.0 version of the CNAG (Copy Number Analyzer for Affymetrix GeneChip mapping) software package, 21 by comparing SNP probe intensities from patient DNA with those of a sex-matched pooled reference DNA sample (DNA from 10 healthy male individuals). The average resolution of this array platform, described by McMullan et al, 22 is 150-200 kb.…”

Section: Affymetrix Nspi Snp Array Hybridization and Analysismentioning

confidence: 99%

Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy

et al. 2010

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The oxidative phosphorylation (OXPHOS) system is under control of both the mitochondrial and the nuclear genomes; 13 subunits are synthesized by the mitochondrial translation machinery. We report a patient with Cornelia de Lange-like dysmorphic features, brain abnormalities and hypertrophic cardiomyopathy, and studied the genetic defect responsible for the combined OXPHOS complex I, III and IV deficiency observed in fibroblasts. The combination of deficiencies suggested a primary defect associated with the synthesis of mitochondrially encoded OXPHOS subunits. Analysis of mitochondrial protein synthesis revealed a marked impairment in mitochondrial translation. Homozygosity mapping and sequence analysis of candidate genes revealed a homozygous mutation in MRPS22, a gene encoding a mitochondrial ribosomal small subunit protein. The mutation predicts a Leu215Pro substitution at an evolutionary conserved site. Mutations in genes implicated in Cornelia de Lange syndrome or copy number variations were not found. Transfection of patient fibroblasts, in which MRPS22 was undetectable, with the wild-type MRPS22 cDNA restored the amount and activity of OXPHOS complex IV, as well as the 12S rRNA transcript level to normal values. These findings demonstrate the pathogenicity of the MRPS22 mutation and stress the significance of mutations in nuclear genes, including genes that have no counterparts in lower species like bacteria and yeast, for mitochondrial translation defects.

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“…2 Several studies reported causative submicroscopic chromosomal aberrations that were only detectable by chromosomal microarray analysis (CMA) 3 and a consensus statement was published that CMA is recommended as first-tier clinical diagnostic test for patients with DD/ID. 4 Besides the detection of submicroscopic deletions and duplications, SNP microarrays can be used for detection of uniparental disomy (UPD).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide UPD screening in patients with intellectual disability

et al. 2014

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Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. It may occur as isodisomy, heterodisomy or a combination of both and may involve only chromosome segments. UPD can affect each chromosome. The incidence is estimated to be around 1:3500 in live births. Some parts of chromosomes are subject to 'parent-of-origin imprinting' and the phenotypic effect in UPD syndromes is mainly due to functional imbalance of imprinted genes. Isodisomy can result in mutation homozygosity in autosomal-recessive inherited diseases. UPD causes several well-defined imprinting syndromes associated with intellectual disability (ID). Although knowledge on frequency and size of UPDs in patients with unexplained ID remains largely unknown as no efficient genome-wide screening technique was available for detection of both isodisomic and heterodisomic UPDs. SNP microarrays have been proven to be capable to detect UPDs through Mendelian errors. The correct subclassification of UPD requires child-parent trio experiments. To further elucidate the role of UPD in patients with unexplained ID, we analyzed a total of 322 child-parent trios. We were not able to detect UPDs (isodisomies and heterodisomies) within our cohort spanning whole chromosomes or chromosomal segments. We conclude that UPD is rare in patients with unexplained ID.

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Molecular karyotyping of patients with unexplained mental retardation by SNP arrays: A multicenter study

Cited by 66 publications

References 42 publications

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

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

Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy

Genome-wide UPD screening in patients with intellectual disability

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