SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly

Garshasbi, Masoud; Motazacker, Mohammad Mahdi; Kahrizi, Kimia; Behjati, Farkhondeh; Abedini, Seyedeh Sedigheh; Nieh, Sahar Esmaeeli; Firouzabadi, Saghar Ghasemi; Becker, Christian; Rüschendorf, Franz; Nürnberg, Peter; Tzschach, Andreas; Vazifehmand, Reza; Erdogan, Fikret; Ullmann, Reinhard; Lenzner, Steffen; Kuß, Andreas W.; Ropers, Hans‐Hilger; Najmabadi, Hossein

doi:10.1007/s00439-005-0104-y

Cited by 66 publications

(64 citation statements)

References 22 publications

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“…Homozygous loss of function mutations of the MCPH1 gene (OMIM 607117, 606858, and 251200) cause autosomal recessive disorders including premature chromosome condensation syndrome, 42 intellectual disability, 42 and microcephaly. 43 Heterozygous deletions and duplications of MCPH1 have been reported in families with autism spectrum disorders, supporting the concept that MCPH1 is a dosage-sensitive gene, with considerable mutation pleiotropy. 44 (vi) A 64-kb duplication of MC2R identified in case P053.…”

Section: Discussionmentioning

confidence: 85%

Rare copy number variation in cerebral palsy

et al. 2013

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Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (o1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in o0.1% (o8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.

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Section: Discussionmentioning

confidence: 85%

Rare copy number variation in cerebral palsy

et al. 2013

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“…Heterozygous deletions of genes in this pathway give rise to the 3 established haploinsufficiency disorders of blepharophimosis-ptosisepicanthus inversus syndrome (MIM 110100), Miller- Dieker syndrome (MIM 247200), and Williams-Beuren syndrome (OMIM 194050) [Torniero et al, 2008]. This suggests that MCPH1 may be a dosage sensitive gene in which a heterozygous deletion or duplication of the whole gene or of the promoter and 5 exons is sufficient to cause autistic symptoms even with mild microcephaly [Garshasbi et al, 2006]. It is also conceivable that CNVs of partial copies of MCPH1 exert a dominant negative effect.…”

Section: Phenotypic Pleiotropy Depending On the Type Of Cnv Or Mutationmentioning

confidence: 99%

“…Recently, several reports have indicated pleiotropic effects of autosomal recessive Microcephalin (MCPH1) mutations (MIM:606858 and MIM:251200) or homozygous 5 deletions [Garshasbi et al, 2006;Darvish et al, 2010]. MCPH1 , being located in chromosomal region 8p23.1, is frequently subject of deletions and duplications Hollox et al, 2008].…”

Section: Phenotypic Pleiotropy Depending On the Type Of Cnv Or Mutationmentioning

confidence: 99%

Disentangling the Myriad Genomics of Complex Disorders, Specifically Focusing on Autism, Epilepsy, and Schizophrenia

Poot

Smagt

Brilstra

et al. 2011

Cytogenet Genome Res

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Analyses of structural genome variation by array-CGH have dramatically enhanced our ability to detect copy number variations (CNVs). De novo CNVs and those co-segregating with disease in a family are generally interpreted as pathogenic. Yet, often CNVs, such as recurrent microdeletions in region 15q13.3, are not so clearly pathogenic. Here we discuss potential confounding mechanisms that may lead to the phenotypic pleiotropy of CNVs, such as unmasking of recessive alleles by hemizygous deletions, interaction of CNVs with other loci and genes, genetic epistasis, allelic exclusion, and somatic mosaicism. We illustrate some of these mechanisms with a detailed analysis of recent studies of CNVs involving MCPH1, AUTS2, CNTNAP2, and mutations in GRIN2B. Next we discuss the clinical ramifications of these findings and urge workers to avoid ‘diagnostic fatalism’ (i.e., halting all genetic investigation after the detection of a single CNV) and address some of the future challenges likely to result from implementations of next generation sequencing techniques.

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“…3,4 All investigations were carried out with the written consent of the parents. For VLDLR mutation screening, primer sequences (available upon request) were generated for all coding and adjacent splice site regions using the ExonPrimer software (http://ihg.gsf.de/ihg/ExonPrimer.html).…”

Section: Methodsmentioning

confidence: 99%

Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome

et al. 2007

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We have investigated a consanguineous Iranian family with eight patients who suffer from mental retardation, disturbed equilibrium, walking disability, strabismus and short stature. By autozygosity mapping we identified one region with a significant LOD score on chromosome 9(p24.2 -24.3). The interval contains the VLDLR gene, which codes for the very low-density lipoprotein receptor. This protein is part of the reelin signalling pathway, which is involved in neuroblast migration in the cerebral cortex and cerebellum. A homozygous deletion encompassing VLDLR has previously been found to cause a syndrome of cerebellar ataxia and mental retardation associated with cerebellar hypoplasia in the Hutterite population known as dysequilibrium syndrome (DES). The reported deletion however, contains an additional brain expressed gene of unknown function, whose involvement in the aetiology of the phenotype could so far not be excluded. We screened the coding region of VLDLR for mutations in our patients and found a homozygous c.1342C4T nucleotide substitution, which leads to a premature stop codon in exon 10. This is the first report of a mutation in patients with DES that affects VLDLR exclusively, confirming the central role of the very low-density lipoprotein receptor in the aetiology of this condition.

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SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly

Cited by 66 publications

References 22 publications

Rare copy number variation in cerebral palsy

Rare copy number variation in cerebral palsy

Disentangling the Myriad Genomics of Complex Disorders, Specifically Focusing on Autism, Epilepsy, and Schizophrenia

Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome

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