皮质发育不良伴其他脑畸形——变异重评估与生育咨询案例实践

Case practice of variant re-evaluation and fertility consultation in cortical dysplasia associated with other brain malformations

目的孕妇已产一孩全面发育落后,现再次怀孕需求生育咨询与指导。方法先证者已行儿童发育评估、颅脑MRI平扫和全外显子组家系检测,现依据ACMG/AMP变异分类指南以及ClinGen补充建议对先证者基因报告进行重新评估。结果家系全外显子组测序发现TUBB3(NM_006086.4)基因新发意义不明变异,即c.86G>A(p.Gly29Asp),经变异致病性重评估后,该变异评级为疑似致病,该变异既往未见文献报道。结合临床表型、变异致病性、致病机制、遗传模式等并经多学科团队会诊,先证者考虑为皮质发育不良伴其他脑畸形Ⅰ型。结论针对临床意义不明基因报告进行重新评估,可提高诊断效益,对再生育咨询与指导具有重要价值。

Objective To provide reproductive counseling and guidance for a pregnant woman who previously had a child with comprehensive developmental delays.Methods The proband has undergone a child development assessment,brain MRI scan,and whole-exome sequencing for the family.Based on the ACMG/AMP variant classification guidelines and supplementary recommendations from ClinGen,the proband's genetic report was re-evaluated.Results Whole-exome sequencing of the family identified a novel variant of uncertain significance in the TUBB3 gene(NM_006086.4),c.86G>A(p.Gly29Asp).After re-evaluating the pathogenicity of the variant,it was classified as likely pathogenic.This variant has not been previously reported in the literature.Considering the clinical phenotype,variant pathogenicity,pathogenic mechanism,inheritance pattern,and after a multidisciplinary team consultation,the proband was considered to have cortical dysplasia with other brain malformations type I.Conclusion Re-evaluating genetic reports with unclear clinical significance can improve diagnostic yield and provide valuable guidance for reproductive counseling.