Familial study of spinal muscular atrophy carriers with SMN1 (2+0) genotype.

Spinal muscular atrophy (SMA) is a common childhood neuromuscular disease inherited in an autosomal recessive pattern. The majority of SMA patients have a homozygous deletion of survival motor neuron 1 (SMN1) gene. As a special SMA carrier, the (2+0) genotype ofSMN1 poses a great challenge for carrier screening and family genetic counseling. A previous study showed that polymorphisms of g.27134 T>G and g.27706_27707delAT had a predictive effect on (2+0) carriers in the Ashkenazi Jewish population. To further explore whether these two polymorphisms are specific to the Chinese population, the present study recruited 44 family members and 204 controls with knownSMN1copy number. These 44 family members were from nine unrelated SMA families withSMN1 homozygous deletion, and one of the proband parents was suspected to be a (2+0) carrier. Multiplex ligation-dependent probe amplification (MLPA) and short tandem repeat (STR) linkage analyses were used to determine the (2+0) genotype and polymorphism screening. Finally, by analyzing theSMN copies and haplotype from three generations of family members and two generations of multi-child families, ten individuals in nine families were confirmed as (2+0) carriers. Moreover, only one individual with three copies ofSMN1 carried the two polymorphisms of g.27134 T>G and g.27706_27707delAT. Therefore, we provided precise genetic counseling for these SMA families after confirming the (2+0) carriers. The association between the polymorphisms of g.27134T>G and g.27706_27707delAT and Chinese (2+0) carriers might be weak. Hence, it is necessary to find specific polymorphisms in the Chinese population to improve the detection rate of (2+0) carriers.脊髓性肌萎缩症(spinal muscular atrophy, SMA)是一种儿童时期较为常见的神经肌肉病,属于常染色体隐性遗传。绝大多数SMA由运动神经元存活基因1 (survival motor neuron 1,SMN1)的纯合缺失突变所致。而SMN1的2+0基因型个体作为一种特殊的SMA携带者,给携带者筛查以及家系的遗传咨询带来了巨大的挑战。已有研究表明,g.27134T>G和g.27706_27707delAT多态位点变异对于Ashkenazi犹太人群中的2+0基因型个体具有提示作用。为进一步探究这两个多态位点是否在中国人群也具有特异性,本研究纳入了44例家系成员和204例已知SMN1基因拷贝数的对照样本。44例家系成员来自于9个无关的SMN1基因纯合缺失的SMA家系,先证者双亲之一疑似为2+0基因型携带者。利用多重连接探针扩增(multiplex ligation-dependent probe amplification, MLPA)和短串联重复(short tandem repeat, STR)连锁分析进行基因型的鉴定以及多态位点的筛查,最终通过对家系三代成员或多子女家系两代成员的分析确定了9个家系中的10例个体为2+0基因型携带者,多态位点筛查显示1例携带3拷贝SMN1基因的个体同时存在g.27134T>G和g.27706_27707delAT多态位点的变异。因此,本研究通过对2+0基因型携带者的鉴定,为家系遗传病的诊断提供了精准的遗传咨询。g.27134T>G和g.27706_27707delAT多态位点可能与中国人群2+0基因型个体的关联度较低,尚需寻找中国人群特异的多态位点以提高2+0基因型携带者的检出率。.