母源性染色体内插入致18q21.2-q22.3重复和缺失后代家系的遗传学分析

Genetic analysis of a Chinese pedigree with 18q21.2-q22.3 duplication and deletion in two offspring respectively resulting from a maternal intrachromosomal insertion

目的为1例具有全面发育障碍患儿生育史的孕妇提供产前诊断、家系分析和遗传咨询。方法选取2021年8月在西南医科大学附属医院接受产前诊断的孕妇作为研究对象,采集先证者、孕妇及其丈夫的外周血样以及胎儿的羊水样本,对其进行G显带染色体核型分析以及基因组拷贝数变异测序(CNV-seq),根据美国医学遗传学与基因组学学会(ACMG)相关指南判读变异的致病性,通过家系分析对变异进行溯源,并评估其再发风险。结果孕妇、胎儿、先证者的染色体核型依次为46,XX,ins(18)(p11.2q21q22)、46,X?,rec(18)dup(18)(q21q22)ins(18)(p11.2q21q22)mat和46,XY,rec(18)del(18)(q21q22)ins(18)(p11.2q21q22)mat,孕妇丈夫染色体核型未见异常。CNV-seq检测提示胎儿18q21.2-q22.3区存在19.73 Mb重复,先证者18q21.2-q22.3区存在19.77 Mb缺失。重复和缺失片段均与孕妇染色体的插入片段相同。根据ACMG指南,均评估为致病性变异。结论孕妇携带的18q21.2-q22.3染色体内插入导致了2个子代18q21.2-q22.3区的重复和缺失。上述结果为该家系的遗传咨询提供了依据。

Objective To provide prenatal diagnosis,pedigree analysis and genetic counseling for a pregnant woman who had given birth to a child featuring global developmental delay.Methods A pregnant woman who underwent prenatal diagnosis at the Affiliated Hospital of Southwest Medical University in August 2021 was selected as the study subject.Peripheral blood samples were collected from the woman,her husband and child,in addition with amniotic fluid sample during mid-pregnancy.Genetic variants were detected by G-banded karyotyping analysis and copy number variation sequencing(CNV-seq).Pathogenicity of the variant was predicted based on the guidelines from the American College of Medical Genetics and Genomics(ACMG).Candidate variant was traced in the pedigree to assess the recurrence risk.Results The karyotypes of the pregnant woman,her fetus,and affected child were 46,XX,ins(18)(p11.2q21q22),46,X?,rec(18)dup(18)(q21q22)ins(18)(p11.2q21q22)mat and 46,XY,rec(18)del(18)(q21q22)ins(18)(p11.2q21q22)mat,respectively.Her husband was found to have a normal karyotype.CNV-seq has revealed a 19.73 Mb duplication at 18q21.2-q22.3 in the fetus and a 19.77 Mb deletion at 18q21.2-q22.3 in her child.The duplication and deletion fragments were identical to the insertional fragment in the pregnant woman.Based on the ACMG guidelines,the duplication and deletion fragments were both predicted to be pathogenic.Conclusion The intrachromosomal insertion of 18q21.2-q22.3 carried by the pregnant woman had probably given rise to the 18q21.2-q22.3 duplication and deletion in the two offspring.Above finding has provided a basis for genetic counseling for this pedigree.