J Med Genet. 2010 Jul;47(7):492-8. doi: 10.1136/jmg.2009.070730. Epub 2009 Dec 2.
IGF1R (insulin-like growth factor 1 receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype-phenotype correlations, although short stature is its well established hallmark. Several pure 15q26 monosomies (n=22) have been described in the literature, including those with breakpoints proximal to the IGF1R gene. Clinical heterogeneity is characteristic for these mainly de novo telomeric deletions and is illustrated by the involvement of several different organ systems such as the heart, diaphragm, lungs, kidneys and limbs, besides growth failure in the patient's phenotype. The clinical variability in these patients could be explained by the haploinsufficiency of multiple genes besides the IGF1R gene. In comparison, the six different IGF1R mutations revealed to date exhibit some variance in their clinical features as well, probably because different parts of the downstream IGF1R signalling cascade were affected.
Using the recently developed technique multiplex ligation dependent probe amplification (MLPA), a chromosome 15q26.3 microdeletion harbouring part of the IGF1R gene was identified in a Dutch family. This deletion segregated with short height in seven out of 14 relatives across three generations. Metaphase fluorescence in situ hybridisation (FISH) and Affymetrix 250k single nucleotide polymorphism (SNP) microarray were used to characterise the deletion into more detail and showed that exons 11-21 of the IGF1R and a small hypothetical protein (LOC 145814) were deleted.
Clinical work-up of this newly identified family, which constitutes the smallest (0.095 Mb) pure 15q26.3 interstitial deletion to date, confirms that disruption of the IGF1R gene does not induce major organ malformation or severe mental retardation.
IGF1R（胰岛素样生长因子 1 受体）杂合不足是一种罕见的事件，导致难以明确确定基因型-表型相关性，尽管身材矮小是其明确的标志。文献中已经描述了几种纯 15q26 单体（n=22），包括那些靠近 IGF1R 基因的断裂点。这些主要从头端端粒缺失的临床异质性是特征，并通过涉及心脏、横膈膜、肺、肾脏和四肢等几个不同的器官系统以及患者表型中的生长失败来说明。这些患者的临床变异性可以通过 IGF1R 基因以外的多个基因的杂合不足来解释。相比之下，迄今为止发现的六种不同的 IGF1R 突变也表现出其临床特征的一些差异，这可能是因为下游 IGF1R 信号级联的不同部分受到了影响。
使用最近开发的多重连接依赖性探针扩增（MLPA）技术，在一个荷兰家庭中鉴定出了一个含有部分 IGF1R 基因的 15q26.3 微缺失。该缺失在三代的 14 个亲属中的 7 个中与身高矮小共分离。中期荧光原位杂交（FISH）和 Affymetrix 250k 单核苷酸多态性（SNP）微阵列用于更详细地描述缺失，并显示 IGF1R 的外显子 11-21 和一个小的假设蛋白（LOC 145814）缺失。
对这个新鉴定的家族进行临床检查，该家族构成了迄今为止最小的（0.095 Mb）纯 15q26.3 间质性缺失，证实 IGF1R 基因的破坏不会导致主要的器官畸形或严重的智力迟钝。
