A follow-up cohort study on secondary findings in cancer predisposition genes from 20,205 Chinese individuals

With the increasing use of next-generation sequencing, secondary findings (SFs) in cancer predisposition genes (CPGs) are being detected more frequently. However, evidence on clinical follow-up, cascade testing, and psychosocial impact in pediatric referral settings remains limited.

We retrospectively analyzed whole-exome sequencing data from 20,205 non-cancer individuals who underwent testing at Shanghai Children's Medical Center between 2014 and 2025 to identify SFs in 28 predefined CPGs. Probands with SFs received confirmatory testing and family-based cascade testing, then clinical follow-up including family health assessment and a structured psychosocial counseling questionnaire.

A total of 67 pathogenic or likely pathogenic (P/LP) variants were identified in 84 probands, yielding an SFs frequency of 0.42% (84/20,205). The cohort included 76 minors and eight adults (median age 10 years; range 1-56). SFs involved nine genes, predominantly BRCA2 (35%), PALB2 (22%), BRCA1 (20%), and Lynch syndrome genes PMS2 (13%) and MSH6 (6%). Most variants were loss-of-function (78%) and inherited (99%, 68/69). Among 47 probands completing follow-up, 26 reported family cancer history, with 15 potentially concordant with the SFs. Of 33 questionnaire respondents, 13 reported anxiety, yet all perceived health management benefits.

Disclosing SFs enabled genetic counseling, cascade testing, and risk-informed management for probands and at-risk relatives. The germline P/LP variant spectrum and curated pedigrees provide resources for penetrance research and may inform pediatric SF return strategies.