Abstract：
Homozygous or compound heterozygous variants in the KLHL40 gene cause nemaline myopathy 8 (NEM8), a severe autosomal recessive muscle disorder characterized by prenatal polyhydramnios, fetal akinesia or hypokinesia, joint contractures, fractures, respiratory failure and dysphagia. Currently, 46 individuals with NEM8 have been described in the literature, and 30 variants in KLHL40 have been identified.
Here, we reported five individuals from four unrelated Chinese families who presented common features of nemaline myopathy and infrequent clinical characteristics. Whole-exome sequencing (WES) was used to identify the causative gene. WES identified a recurrent missense variant c.1516A>C (p.Thr506Pro) and a novel frameshift variant c.543del (p.Ser182Profs*17) in KLHL40 in patient 1, a nonsense variant c.602G>A (p.Trp201*) and a missense variant c.1516A>C (p.Thr506Pro) in KLHL40 in patient 2, and homozygous variant c.1516A>C (p.Thr506Pro) in KLHL40 in patient 3 and both siblings (patients 4 and 5), all of which were confirmed by Sanger sequencing. Next, we estimated the incidence of this disorder in the southern and northern Chinese population to be 4.59/106 and 2.95/106, respectively, based on the cumulative allele frequency of pathogenic variants in internal database.
The results of our study expand the mutation spectrum of KLHL40 and enrich our understanding of the clinical characteristics of NEM8. Genetic counseling was provided for the four families involved in this study. Given the severity and the relatively high incidence of this condition, we strongly suggest that KLHL40 be incorporated into a carrier screening panel for the Chinese population.
Here, we reported five individuals from four unrelated Chinese families who presented common features of nemaline myopathy and infrequent clinical characteristics. Whole-exome sequencing (WES) was used to identify the causative gene. WES identified a recurrent missense variant c.1516A>C (p.Thr506Pro) and a novel frameshift variant c.543del (p.Ser182Profs*17) in KLHL40 in patient 1, a nonsense variant c.602G>A (p.Trp201*) and a missense variant c.1516A>C (p.Thr506Pro) in KLHL40 in patient 2, and homozygous variant c.1516A>C (p.Thr506Pro) in KLHL40 in patient 3 and both siblings (patients 4 and 5), all of which were confirmed by Sanger sequencing. Next, we estimated the incidence of this disorder in the southern and northern Chinese population to be 4.59/106 and 2.95/106, respectively, based on the cumulative allele frequency of pathogenic variants in internal database.
The results of our study expand the mutation spectrum of KLHL40 and enrich our understanding of the clinical characteristics of NEM8. Genetic counseling was provided for the four families involved in this study. Given the severity and the relatively high incidence of this condition, we strongly suggest that KLHL40 be incorporated into a carrier screening panel for the Chinese population.
摘要：
KLHL40基因中的纯合或复合杂合变体导致线虫肌病8（NEM8），一种以产前羊水过多为特征的严重常染色体隐性肌肉疾病，胎儿运动障碍或运动功能减退，关节挛缩,骨折,呼吸衰竭和吞咽困难。目前,文献中已经描述了46例NEM8患者，已经鉴定出KLHL40中的30种变体。
这里,我们报道了来自4个不相关的中国家庭的5名患者,他们表现出线虫性肌病的共同特征和罕见的临床特征.使用全外显子组测序(WES)来鉴定致病基因。WES确定了一个复发性错义变体c.1516A>C（p。Thr506Pro）和一种新颖的移码变体c.543del（p。Ser182Profs*17）在患者1的KLHL40中，无意义变体c.602G>A（p。Trp201*）和一个错义变体c.1516A>C（第Thr506Pro）在患者2的KLHL40中，纯合变体c.1516A>C（p。Thr506Pro）在KLHL40患者3和两个兄弟姐妹（患者4和5）中，所有这些均通过Sanger测序证实.接下来,我们估计这种疾病在中国南方和北方人群中的发病率分别为4.59/106和2.95/106,基于内部数据库中致病变异的累积等位基因频率。
我们的研究结果扩展了KLHL40的突变谱，丰富了我们对NEM8临床特征的理解。为参与这项研究的四个家庭提供了遗传咨询。鉴于这种情况的严重性和相对较高的发生率，我们强烈建议将KLHL40纳入中国人群的载体筛查小组.
这里,我们报道了来自4个不相关的中国家庭的5名患者,他们表现出线虫性肌病的共同特征和罕见的临床特征.使用全外显子组测序(WES)来鉴定致病基因。WES确定了一个复发性错义变体c.1516A>C（p。Thr506Pro）和一种新颖的移码变体c.543del（p。Ser182Profs*17）在患者1的KLHL40中，无意义变体c.602G>A（p。Trp201*）和一个错义变体c.1516A>C（第Thr506Pro）在患者2的KLHL40中，纯合变体c.1516A>C（p。Thr506Pro）在KLHL40患者3和两个兄弟姐妹（患者4和5）中，所有这些均通过Sanger测序证实.接下来,我们估计这种疾病在中国南方和北方人群中的发病率分别为4.59/106和2.95/106,基于内部数据库中致病变异的累积等位基因频率。
我们的研究结果扩展了KLHL40的突变谱，丰富了我们对NEM8临床特征的理解。为参与这项研究的四个家庭提供了遗传咨询。鉴于这种情况的严重性和相对较高的发生率，我们强烈建议将KLHL40纳入中国人群的载体筛查小组.
