BACKGROUND Spinal muscular atrophy (SMA) is a rare neuromuscular disorder threating hundreds of thousands of lives worldwide. And the severity of SMA differs among different clinical types, which has been demonstrated to be modified by factors like SMN2, SERF1, NAIP, GTF2H2 and PLS3. However, the severities of many SMA cases, especially the cases within a family, often failed to be explained by these modifiers. Therefore, other modifiers are still waiting to be explored. CASE PRESENTATION In this study, we presented a rare case of SMA discordant family with a mild SMA male patient and a severe SMA female patient. The two SMA cases fulfilled the diagnostic criteria defined by the International SMA Consortium. With whole exome sequencing, we confirmed the heterozygous deletion of exon7 at SMN1 on the parents' genomes and the homozygous deletions on the two patients' genomes. The MLPA results confirmed the deletions and indicated that all the family members carry two copies of SMN2, SERF1, NAIP and GTF2H2. Further genomic analysis identified compound heterozygous mutations at TLL2 on the male patient's genome, and compound heterozygous mutations at VPS13A and the de novo mutation at AGAP5 on female patient's genome. TLL2 is an activator of myostatin, which negatively regulates the growth of skeletal muscle tissue. Mutation in TLL2 has been proved to increase muscular function in mice model. VPS13A encodes proteins that control the cycling of proteins through the trans-Golgi network to endosomes, lysosomes and the plasma membrane. And AGAP5 was reported to have GTPase activator activity. CONCLUSIONS We reported a case of SMA discordant family and identified mutations at TLL2, VPS13A and AGAP5 on the patients' genomes. The mutations at TLL2 were predicted to be pathogenic and are likely to alleviate the severity of the male SMA patient. Our finding broadens the spectrum of genetic modifiers of SMA and will contribute to accurate counseling of SMA affected patients and families.

中文翻译：

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脊柱肌肉萎缩症（SMA）不和谐家族的基因组分析确定了TLL2的新突变，TLL2是生长分化因子8（myostatin）的激活剂：一例病例报告。

背景技术脊髓性肌萎缩症（SMA）是一种罕见的神经肌肉疾病，威胁着全世界成千上万的生命。SMA的严重程度在不同的临床类型之间也有所不同，这已被SMN2，SERF1，NAIP，GTF2H2和PLS3等因素所修饰。但是，许多SMA病例的严重程度，尤其是一个家庭中的病例，常常无法用这些修饰语来解释。因此，其他修饰符仍在等待探索中。病例介绍在这项研究中，我们介绍了SMA不和谐家庭的一例，其中有一名轻度SMA男性患者和一名重度SMA女性患者。这两个SMA病例符合国际SMA联合会定义的诊断标准。通过完整的外显子组测序，我们确认了父母的SMN1上exon7的杂合缺失 基因组和两名患者基因组上的纯合缺失。MLPA结果证实了缺失，并表明所有家族成员均携带SMN2，SERF1，NAIP和GTF2H2的两个副本。进一步的基因组分析确定了男性患者基因组上TLL2处的化合物杂合突变，以及女性患者基因组上VPS13A处的化合物杂合突变和AGAP5处的从头突变。TLL2是肌生长抑制素的激活剂，它负面调节骨骼肌组织的生长。已经证明TLL2的突变在小鼠模型中增加了肌肉功能。VPS13A编码控制通过反高尔基网络到达内体，溶酶体和质膜的蛋白质循环的蛋白质。并且据报道AGAP5具有GTPase激活剂活性。结论我们报道了一例SMA不和谐家族，并在患者基因组上鉴定了TLL2，VPS13A和AGAP5突变。预计TLL2处的突变具有致病性，并可能减轻男性SMA患者的严重程度。我们的发现拓宽了SMA基因修饰物的范围，并将有助于为SMA受影响的患者和家庭提供准确的咨询。