20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits.

BACKGROUND: Wolff-Parkinson-White syndrome (WPW) is a bypass re-entrant tachycardia that results from an abnormal connection between the atria and ventricles. Mutations in PRKAG2 have been described in patients with familial WPW syndrome and hypertrophic cardiomyopathy. Based on the role of bone morphogenetic protein (BMP) signalling in the development of annulus fibrosus in mice, it has been proposed that BMP signalling through the type 1a receptor and other downstream components may play a role in pre-excitation. METHODS AND RESULTS: Using the array comparative genomic hybridisation (CGH), we identified five individuals with non-recurrent deletions of 20p12.3. Four of these individuals had WPW syndrome with variable dysmorphisms and neurocognitive delay. With the exception of one maternally inherited deletion, all occurred de novo, and the smallest of these harboured a single gene, BMP2. In two individuals with additional features of Alagille syndrome, deletion of both JAG1 and BMP2 were identified. Deletion of this region has not been described as a copy number variant in the Database of Genomic Variants and has not been identified in 13 321 individuals from other cohort examined by array CGH in our laboratory. CONCLUSIONS: Our findings demonstrate a novel genomic disorder characterised by deletion of BMP2 with variable cognitive deficits and dysmorphic features and show that individuals bearing microdeletions in 20p12.3 often present with WPW syndrome.

Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), encoding components of the sister chromatid cohesion apparatus, are responsible for approximately 50-60% of CdLS cases. Recent studies have revealed a high degree of genomic rearrangements (for example, deletions and duplications) in the human genome, which result in gene copy number variations (CNVs). CNVs have been associated with a wide range of both Mendelian and complex traits including disease phenotypes such as Charcot-Marie-Tooth type 1A, Pelizaeus-Merzbacher, Parkinson, Alzheimer, autism and schizophrenia. Increased versus decreased copy number of the same gene can potentially cause either similar or different clinical features. METHODS AND RESULTS: This study identified duplications on chromosomes 5 or X using genome wide array comparative genomic hybridisation (aCGH). The duplicated regions contain either the NIPBL or the SMC1A genes. Junction sequences analyses revealed the involvement of three genomic rearrangement mechanisms. The patients share some common features including mental retardation, developmental delay, sleep abnormalities, and craniofacial and limb defects. The systems affected are the same as in CdLS, but clinical manifestations are distinct from CdLS; particularly the absence of the CdLS facial gestalt. CONCLUSIONS: The results confirm the notion that duplication CNV of genes can be a common mechanism for human genetic diseases. Defining the clinical consequences for a specific gene dosage alteration represents a new "reverse genomics" trend in medical genetics that is reciprocal to the traditional approach of delineation of the common clinical phenotype preceding the discovery of the genetic aetiology.

BAC contig from a 3-cM region of mouse chromosome 11 surrounding Brca1.

Even with the completion of a draft version of the human genome sequence only a fraction of the genes identified from this sequence have known functions. Chromosomal engineering in mouse cells, in concert with gene replacement assays to prove the functional significance of a given genomic region or gene, represents a rapid and productive means for understanding the role of a given set of genes. Both techniques rely heavily on detailed maps of chromosomal regions, initially to understand the scope of the regions being modified and finally to provide the cloned resources necessary to allow both finished sequencing and large insert complementation. This report describes the creation of a BAC clone contig on mouse chromosome 11 in a region showing conservation of synteny with sequences on human chromosome 17. We have created a detailed map of an approximately 3-cM region containing at least 33 genes through the use of multiple BAC mapping strategies, including chromosome walking and multiplex oligonucleotide hybridization and gap filling. The region described is one of the targets of a large effort to create a series of mice with regional deletions on mouse chromosome 11 (33-80 cM) that can subsequently be subjected to further mutagenesis.

Fine mapping of MEP1A, the gene encoding the alpha subunit of the metalloendopeptidase meprin, to human chromosome 6P21.

Meprins are kidney and intestinal proteases encoded by two distinct genes, MEP1A and MEP1B. MEP1A was previously mapped to human chromosome 6p, by the use of radiation and somatic cell hybrids, in the region containing the gene for autosomal recessive polycystic kidney disease (ARPKD). We now report the fine mapping of MEP1A using yeast artificial chromosome clones, and linkage analysis of ARPKD families. The results from both physical and genetic mapping exclude MEP1A as a candidate for ARPKD. These studies place MEP1A in a region more telomeric to 6p12 and closer to the HLA loci than previously reported. More specifically, MEP1A is localized between loci D6S272 and D6S282, close to D6S452, on human chromosome 6p21.2-p21.1. The more precise location of MEP1A will facilitate genetic studies of this locus and clarify the relation of this gene to others.