Mutation analysis of H19 and NAP1L4 (hNAP2) candidate genes and IGF2 DMR2 in Beckwith-Wiedemann syndrome

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Abstract
Editor—Beckwith-Wiedemann syndrome (BWS) is a human overgrowth disorder with a variable phenotype and genetic heterogeneity. Recent data indicate that the BWS locus is subject to genomic imprinting and current evidence shows that in many patients the disease is associated with epigenetic lesions of genes on 11p15.5. BWS is characterised by pre- and postnatal overgrowth, macroglossia, and anterior abdominal wall defects. Additional, but variable complications include organomegaly, hypoglycaemia, hemihypertrophy, genitourinary abnormalities, and a predisposition to embryonal tumours in about 5% of patients.1 The genetics of BWS are complex, but parent of origin effects, suggesting genomic imprinting, have been implicated in the pathogenesis of three major groups of patients2: (1) for patients (∼2%) with chromosome 11p15.5 abnormalities, duplications are of paternal origin and balanced translocations or inversion breakpoints of maternal origin; (2) in familial cases (∼15% of all cases) which exhibit more complete penetrance with maternal transmission; and (3) approximately 20% of sporadic cases have uniparental disomy (paternal isodisomy) for chromosome 11p15.5. Cloning of genes in the vicinity of BWSCR1, the most distal breakpoint cluster associated with BWS balanced cytogenetic anomalies, and within the area of minimal disomy present in cases of paternal isodisomy, has led to the identification of a group of genes as potential candidates in the aetiopathology of BWS. Thus, multiple imprinted genes bounded centromerically by NAP1L4 and telomerically by L23mrp ( RPL23L ) have been identified.3-6 For a gene to be a good candidate to account for a significant number of BWS cases, it should map to this region and constitute either a paternally expressed growth promoter or a maternally expressed growth inhibitor. However, because factors involved in maintaining or modifying genomic imprints may affect the epigenotype and therefore expression status of imprinted genes, it is possible that an underlying lesion in a non-imprinted …