Identifying the genetic etiology of a child with Bainbridge-Ropers syndrome

Abstract:

Objective：To analyze the genetic etiology of a child affected by severely developmental delay，atrial septal defect and a series of complicated phenotypes. Methods：The child has undergone history taking and physical examination. Genome DNA was extracted from peripheral blood samples of the proband and his parents. Candidate genes were captured with Agilent SureSelect and sequenced on an lllumina platform. Suspected mutation was identified and verified by Sanger sequencing. Results：By whole exome sequencing，we found a heterozygous frameshift mutation in proband’s ASXL3 gene（ASXL3；c.1349dupT；p.I450fs） and identified it as pathogenic variant according to the ACMG standards and guidelines for the interpretation of sequence variants. And our candidate has cartilaginous ossification of larynx and dorsiflexion of finger，which are never been reported in other Bainbridge-Ropers syndrome（BRS） patients. Meanwhile，we found a reported mital valve prolapsed 2（MVP2） pathogenic variant DCHS1；c.G7538A；p.R2513H. The function of this variant has been proved by cell and animal experiments. The knock-out of DCHS1 in zebra fish resulted in a cardiac atrioventricular canal defect and the atrial septal defect in our proband could also be attributed to DCHS1 mutation. The proband’s mutant is inherited from his father，however no cardiac function and structure abnormality were observed in his father by ultrasonic cardiogram and electrocardiogram. This might be due to nonpenetrance. Conclusion：Our study broadened the mutant and phenotype spectrum of ASXL3. And we reported the first Bainbridge-Ropers patient with other pathogenic variant.