Evaluating the Diagnostic Yield of Prenatal Trio Exome Sequencing in Families With a History of Developmental Delay and Intellectual Disability

Evaluate the application efficacy of trio exome sequencing (Trio-ES) in prenatal families with a history of developmental delay/intellectual disability (DD/ID). This cohort study enrolled prenatal families with a family history of DD/ID from a single center between January 2020 and May 2025. We included 104 prenatal families that had excluded copy number variation abnormalities but had not undergone single nucleotide variant testing. Based on family history, these families were divided into two groups: those with a history of DD/ID births but phenotypically normal parents (lacking proband samples), and those without a history of DD/ID births but with one or both parents having ID. The overall positive rate of prenatal Trio-ES among 104 families with a history of DD/ID was 21.15% (22/104). Among 81 families with a history of DD/ID births but phenotypically normal parents, the positive rate was 13.58% (11/81), including 7.41% (6/81) affected fetuses and 6.17% (5/81) only parents as carriers, both primarily exhibiting a recessive inheritance pattern. Additionally, the positive rate in non-syndromic DD/ID families was 11.54% (6/52), while it reached 17.24% (5/29) in syndromic DD/ID families (associated with epilepsy, dystonia, hearing impairment, abnormal head circumference, etc.). Among 23 families without a history of DD/ID births but with one or both parents having ID, the positive rate significantly increased to 47.83% (11/23), primarily driven by dominant variants. This study represents the first focused evaluation of the clinical utility of Trio-ES in prenatal families with a history of DD/ID when proband samples are unavailable. We recommend actively employing Trio-ES for prenatal genetic evaluation in such families, particularly those presenting with a syndromic phenotype.