Objective

To perform genotype-phenotype, clinical and molecular analysis in a large 3-generation family with autosomal dominant congenital spinal muscular atrophy.

Methods

Using a combined genetic approach including whole genome scanning, next generation sequencing-based multigene panel, whole genome sequencing, and targeted variant Sanger sequencing, we studied the proband and multiple affected individuals of this family who presented bilateral proximal lower limb muscle weakness and atrophy.

Results

We identified a novel heterozygous variant, c.1826T > C; p.Ile609Thr, in the DYNC1H1 gene localized within the common haplotype in the 14q32.3 chromosomal region which cosegregated with disease in this large family. Within the family, affected individuals were found to have a wide array of clinical variability. Although some individuals presented the typical lower motor neuron phenotype with areflexia and denervation, others presented with muscle weakness and atrophy, hyperreflexia, and absence of denervation suggesting a predominant upper motor neuron disease. In addition, some affected individuals presented with an intermediate phenotype characterized by hyperreflexia and denervation, expressing a combination of lower and upper motor neuron defects.

Conclusion

Our study demonstrates the wide clinical variability associated with a single disease causing variant in DYNC1H1 gene and this variant demonstrated a high penetrance within this large family.

中文翻译：

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DYNC1H1中的一种新型致病变异会导致各种上，下运动神经元异常。

目的

为了在具有常染色体显性先天性脊髓性肌萎缩症的大型3代家庭中进行基因型-表型，临床和分子分析。

方法

使用包括全基因组扫描，基于下一代测序的多基因组，全基因组测序和靶向变异Sanger测序在内的组合遗传方法，我们研究了该家族的先证者和多个受影响的个体，这些个体表现出双侧下肢近端肌肉无力和萎缩。

结果

我们确定了一个新的杂合变体，c.1826T> C；p.Ile609Thr，位于DYNC1H1基因中，位于14q32.3染色体区域的常见单倍型中，与该大家族中的疾病共隔离。在家庭中，发现受影响的个体具有广泛的临床变异性。尽管有些人表现出典型的下运动神经元表型伴反射和神经支配，但另一些人表现出肌肉无力和萎缩，反射亢进和缺乏神经支配，提示上运动神经元疾病占主导地位。另外，一些受影响的个体表现出以反射亢进和神经支配失为特征的中间表型，表现出上下运动神经元缺陷的组合。

结论

我们的研究表明，与DYNC1H1基因的单个致病变异相关的广泛临床变异性，并且该变异表现出该大家族中的高渗透率。