Xu Yuqing, Zhu Linyan, Qian Yeqing, Dong Minyue
Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, China.
Front Pediatr. 2023 Jun 19;11:1191068. doi: 10.3389/fped.2023.1191068. eCollection 2023.
Mutations of gene are associated with congenital muscular dystrophy (CMD). The -related CMD mainly consists of two diseases, merosin deficient congenital muscular dystrophies type 1A (MDC1A) and limb girdle muscular dystrophy 23 (LGMD23). LGMD23 is characterized by slowly progressive proximal muscle weakness, which primarily affects the lower limbs and results in gait difficulties. Additional clinical features include increased serum creatine kinase, abnormal electromyography with or without white matter abnormalities on brain imaging.
Clinical data were collected from a Chinese Han family. Whole-exome sequencing, Sanger sequencing, RT-PCR and TA clone sequencing were performed on the family members.
Compound heterozygous mutations of : c.1693C > T (. Q565*) (maternally inherited) and c.9212-6T > G (paternally inherited) were identified and confirmed in the proband. The mutation c.1693C > T (. Q565*) was classified as pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. By performing RT-PCR and TA clone sequencing, an insertion of 40-bp intronic sequence (intron 64) was found in the transcripts of the proband and her father, which resulted in a frameshift and premature truncation codon of the . In particular, the variant truncated the LamG domain of the LAMA2. Therefore, the c.9212-6T>G was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines.
Our findings described two novel mutations in a girl with LGMDR23, which contributes to the genetic counseling of the family and expands the clinical and molecular spectrums of the rare disease.
基因的突变与先天性肌营养不良（CMD）相关。与该基因相关的CMD主要包括两种疾病，即1A型缺乏层黏连蛋白的先天性肌营养不良（MDC1A）和23型肢带型肌营养不良（LGMD23）。LGMD23的特征是进行性近端肌无力，主要影响下肢并导致步态困难。其他临床特征包括血清肌酸激酶升高、肌电图异常，脑部影像学检查可有或无白质异常。
收集了一个中国汉族家庭的临床资料。对家庭成员进行了全外显子组测序、桑格测序、逆转录聚合酶链反应（RT-PCR）和TA克隆测序。
在先证者中鉴定并确认了该基因的复合杂合突变：c.1693C＞T（.Q565*）（母系遗传）和c.9212-6T＞G（父系遗传）。根据美国医学遗传学与基因组学学会（ACMG）指南，突变c.1693C＞T（.Q565*）被分类为致病性突变。通过RT-PCR和TA克隆测序，在先证者及其父亲的转录本中发现了40个碱基对的内含子序列（第64内含子）插入，这导致了该基因的移码和过早截断密码子。特别是，该变异截断了层黏连蛋白α2（LAMA2）的LamG结构域。因此，根据ACMG指南，c.9212-6T＞G被分类为可能致病性突变。
我们的研究结果描述了一名患有LGMD23女孩的两个新突变，这有助于该家庭的遗传咨询，并扩展了这种罕见疾病的临床和分子谱。
