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Abstract：
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.
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.
摘要：
婴儿恶性石骨症（IMO）是一种罕见的常染色体隐性遗传疾病，其特征是骨吸收功能障碍引起的骨髓骨密度增加。临床上,IMO可以通过体检来诊断，骨密度测试和全基因组测序。
我们介绍了一个4个月大的男婴颅骨发育异常的案例，低钙血症和颅骨缝线过早闭合。由于他的影像学检查显示骨密度过高，这是国际海事组织的特征模式，我们推测他可能是国际海事组织的病人.为了确认这个诊断,对婴儿及其父母进行了高精度全外显子组测序.对高精度全外显子组测序结果的分析导致鉴定出两个新的杂合突变c.504-1G>C（剪接位点突变）和c.1371delC（p。G458Afs*70，一种移码突变）来自其父母的TCIRG1基因。因此,我们认为这两种突变与IMO的发生密切相关。
到目前为止，TCIRG1基因中的这两个新突变在中国人群的参考基因数据库中尚未报道。在中国以外的基因组聚集数据库（gnomAD）中同样没有报道这些变体。我们的案例表明，使用全外显子组测序来检测这两种突变将提高IMO的识别和早期诊断，更具体地说，鉴定具有TCIRG1基因突变的纯合个体。我们认为TCIRG1基因中的这些突变可能是未来IMO的新治疗靶标。
我们介绍了一个4个月大的男婴颅骨发育异常的案例，低钙血症和颅骨缝线过早闭合。由于他的影像学检查显示骨密度过高，这是国际海事组织的特征模式，我们推测他可能是国际海事组织的病人.为了确认这个诊断,对婴儿及其父母进行了高精度全外显子组测序.对高精度全外显子组测序结果的分析导致鉴定出两个新的杂合突变c.504-1G>C（剪接位点突变）和c.1371delC（p。G458Afs*70，一种移码突变）来自其父母的TCIRG1基因。因此,我们认为这两种突变与IMO的发生密切相关。
到目前为止，TCIRG1基因中的这两个新突变在中国人群的参考基因数据库中尚未报道。在中国以外的基因组聚集数据库（gnomAD）中同样没有报道这些变体。我们的案例表明，使用全外显子组测序来检测这两种突变将提高IMO的识别和早期诊断，更具体地说，鉴定具有TCIRG1基因突变的纯合个体。我们认为TCIRG1基因中的这些突变可能是未来IMO的新治疗靶标。
