Eggermann Thomas, Meyer Esther, Caglayan A Okay, Dundar Munis, Schönherr N
Institute of Human Genetics, RWTH Aachen, Germany.
J Pediatr Endocrinol Metab. 2008 Jan;21(1):59-62. doi: 10.1515/jpem.2008.21.1.59.
(Epi)mutations affecting chromosome llp15 are well known to be associated with growth disturbances. The finding of llp15 mutations in the overgrowth disease Beckwith-Wiedemann syndrome led to the identification of imprinted growth-promoting genes which are expressed paternally and of imprinted growth-suppressing genes in the same region that are expressed maternally. An opposite epimutation in the same region is associated with Silver-Russell syndrome (SRS), a growth retardation disorder characterised by a typical facial gestalt, clinodactyly V and asymmetry. In more than 30% of patients with SRS, hypomethylation of the telomeric llp15 imprinting domain (ICR1) can be detected. However, the general significance of this epimutation for human growth retardation was unclear. In a previous study' we showed that the ICR1 epimutation is not present in growth retarded patients with dysmorphisms not typical for SRS, but its role in the development of isolated growth restriction needed to be further elucidated. We therefore screened 30 patients with isolated pre- and postnatal growth retardation (IUGR/PNGR) and 65 patients diagnosed with SRS by external clinicians for ICR1I epimutations. In the latter group clinical data were rarely provided. These 65 'SRS' patients were additionally analysed for maternal uniparental disomy 7 (matUPD7). We excluded ICR1 hypomethylation in all 30 patients with isolated growth retardation. In the SRS group, we detected four cases with ICR1 epimutation and three with matUPD7. By combining our data with those from our previous study we could show that the hypomethylation of ICR1 in llp15 is indeed restricted to patients with SRS features and can be disregarded in isolated IUGR/PNGR. Thus, testing for the epimutation is indicated only in case of growth restriction in association with clinical signs reminiscent of SRS. The low detection rate of the ICR1 epimutation in our 'SRS' group can be explained by the clinical heterogeneity of cases referred by external institutions.
影响染色体11p15的（表观）突变与生长紊乱密切相关。在过度生长疾病贝克威思-维德曼综合征中发现11p15突变，从而鉴定出父系表达的印记促生长基因以及同一区域母系表达的印记生长抑制基因。同一区域的相反表观突变与银-罗素综合征（SRS）相关，这是一种生长发育迟缓疾病，其特征为典型的面部形态、第五指弯曲和不对称。在超过30%的SRS患者中，可检测到端粒11p15印记区域（ICR1）的低甲基化。然而，这种表观突变对人类生长发育迟缓的普遍意义尚不清楚。在之前的一项研究中，我们表明ICR1表观突变不存在于具有非SRS典型畸形的生长发育迟缓患者中，但其在孤立性生长受限发展中的作用仍需进一步阐明。因此，我们对30例孤立性产前和产后生长迟缓（IUGR/PNGR）患者以及65例由外部临床医生诊断为SRS的患者进行了ICR1表观突变筛查。在后一组中，很少提供临床数据。对这65例“SRS”患者还进行了母源单亲二体7（matUPD7）分析。我们在所有30例孤立性生长迟缓患者中均排除了ICR1低甲基化。在SRS组中，我们检测到4例ICR1表观突变和3例matUPD7。通过将我们的数据与之前研究的数据相结合，我们可以表明11p15中ICR1的低甲基化确实仅限于具有SRS特征的患者，在孤立性IUGR/PNGR中可不予考虑。因此，仅在生长受限且伴有提示SRS的临床体征时才建议检测表观突变。我们“SRS”组中ICR1表观突变的低检出率可以用外部机构转诊病例的临床异质性来解释。
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