DataSheet1_Case report: Prenatal diagnosis of fetal intracranial hemorrhage due to compound mutations in the JAM3 gene.ZIP

Intracranial hemorrhage is a common complication in preterm infants but occasionally occurs in fetuses. Disruptions of the genes, such as the COL4A1 and COL4A2 genes, are common genetic causes identified in fetal intracranial hemorrhage; however, the disruptions of the JAM3 gene are rarely reported. In the current investigation, fetal intracranial hemorrhage and dilated lateral ventricles were observed in three consecutive siblings in a pedigree. The pregnancies were terminated, and whole-exome sequencing, followed by Sanger sequencing, was performed on the affected fetuses. Pre-implantation genetic testing for monogenic diseases was performed to avoid the recurrence. The compound heterozygous variants of c.712 + 2T > A and c.813C > G p.Tyr271* in the JAM3 gene (NM_032801.4) were identified in the proband and its affected brother, which were predicted to be pathogenic. The variant of c.813C > G p.Tyr271* but not c.712 + 2T > A was identified in the fourth fetus, implying a good prognosis. Our findings expanded the spectrum of the pathogenic mutations in the JAM3 gene and revealed an important application of fetal whole-exome sequencing in idiopathic fetal intracranial hemorrhage.

颅内出血（intracranial hemorrhage）是早产儿的常见并发症，偶可发生于胎儿。COL4A1基因（COL4A1）与COL4A2基因（COL4A2）等基因的变异是目前已明确的胎儿颅内出血常见遗传病因，但JAM3基因（JAM3）的变异相关报道较为罕见。本研究在一个家系的3名连续妊娠受累胎儿中观察到胎儿颅内出血合并侧脑室扩张。所有妊娠均已终止，研究人员对受累胎儿开展了全外显子测序（whole-exome sequencing），后续通过桑格测序（Sanger sequencing）进行验证。为避免再次出现类似妊娠不良结局，该家系实施了单基因病植入前遗传学检测（pre-implantation genetic testing for monogenic diseases）。先证者（proband）及其受累兄长均检出JAM3基因（NM_032801.4）上c.712 + 2T>A与c.813C>G p.Tyr271*的复合杂合变异，经生物信息学预测该变异为致病性变异。第四名胎儿仅检出c.813C>G p.Tyr271*变异，未检出c.712 + 2T>A变异，提示其预后良好。本研究拓展了JAM3基因致病性突变的变异谱，并揭示了胎儿全外显子测序在特发性胎儿颅内出血中的重要应用价值。