Department of Respirology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
Department of Respirology, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.
BMC Pediatr. 2021 Jul 1;21(1):297. doi: 10.1186/s12887-021-02774-1.
Infantile malignant osteopetrosis (IMO) is a rare autosomal recessive disease characterized by a higher bone density in bone marrow caused by the dysfunction of bone resorption. Clinically, IMO can be diagnosed with medical examination, bone mineral density test and whole genome sequencing.
We present the case of a 4-month-old male infant with abnormal skull development, hypocalcemia and premature closure of the cranial sutures. Due to the hyper bone density showed by his radiographic examination, which are characteristic patterns of IMO, we speculated that he might be an IMO patient. In order to confirm this diagnosis, a high-precision whole exome sequencing of the infant and his parents was performed. The analysis of high-precision whole exome sequencing results lead to the identification of two novel heterozygous mutations c.504-1G > C (a splicing site mutation) and c.1371delC (p.G458Afs*70, a frameshift mutation) in gene TCIRG1 derived from his parents. Therefore, we propose that there is a close association between these two mutations and the onset of IMO.
To date, these two novel mutations in gene TCIRG1 have not been reported in the reference gene database of Chinese population. These variants have likewise not been reported outside of China in the Genome Aggregation Database (gnomAD). Our case suggests that the use of whole exome sequencing to detect these two mutations will improve the identification and early diagnosis of IMO, and more specifically, the identification of homozygous individuals with TCIRG1 gene mutation. We propose that these mutations in gene TCIRG1 could be a novel therapeutic target for the IMO in the future.
婴儿恶性骨硬化症（IMO）是一种罕见的常染色体隐性疾病，其特征是骨髓中的骨密度升高，这是由于骨吸收功能障碍所致。临床上，IMO 可以通过体格检查、骨矿物质密度测试和全基因组测序进行诊断。
我们报告了一例 4 个月大的男性婴儿，其颅骨发育异常、低钙血症和颅缝过早闭合。由于他的影像学检查显示骨密度增高，这是 IMO 的典型表现，我们推测他可能是 IMO 患者。为了确诊，对婴儿及其父母进行了高精度全外显子组测序。婴儿及其父母高精度全外显子组测序结果分析导致鉴定出基因 TCIRG1 中的两个新的杂合突变 c.504-1G>C（剪接位点突变）和 c.1371delC（p.G458Afs*70，移码突变）。因此，我们提出这两个突变与 IMO 的发病密切相关。
迄今为止，TCIRG1 基因中的这两个新突变尚未在中国人参考基因数据库中报道。这些变体在中国外的基因组聚集数据库（gnomAD）中也没有报道。我们的病例表明，使用全外显子组测序检测这两个突变将提高 IMO 的识别和早期诊断，特别是 TCIRG1 基因突变纯合个体的识别。我们提出，TCIRG1 基因中的这些突变可能是 IMO 的一个新的治疗靶点。
