Genomic sequencing identifies secondary findings in a cohort of parent study participants

Abstract

PURPOSE: Clinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability. METHODS: Exome/genome sequencing and analysis of 789 'unaffected' parents was performed. RESULTS: Pathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.2%), with 11 (1.4%) participants harboring variation in a gene defined as clinically actionable by the ACMG. Of the 25 individuals, five carried a variant consistent with a previous clinical diagnosis, thirteen were not previously diagnosed but had symptoms or family history with probable association with the detected variant, and seven reported no symptoms or family history of disease. A limited carrier screen was performed yielding 15 variants in 48 (6.1%) parents. Parents were also analyzed as matepairs to identify cases in which both parents were carriers for the same recessive disease; this led to one finding in ATP7B. Four participants had two findings (one carrier and one non-carrier variant). In total, 71 of the 789 enrolled parents (9.0%) received secondary findings. CONCLUSION:We provide an overview of the rates and types of clinically relevant secondary findings, which may be useful in the design, and implementation of research and clinical sequencing efforts to identify such findings.

Frequency and management of medically actionable incidental findings from genome and exome sequencing data: a systematic review

“…90% of the reviewed articles reported incidental finding frequencies between 0.5% and 6.5% in their studied cohorts and two studies reported a frequency of incidental findings above 12% (9,19). The higher frequency could be partially explained by the use of different gene lists to return the incidental findings; as some studies preferred to include a more comprehensive list of genes with actionable variants (9,13,21,22,41,61).…”

“…Thirteen reviewed articles restricted the analysis of the incidental findings to the 56/59 ACMG genes. The difference between the total reported frequency of participants with incidental findings and the frequency of participants with incidental findings in the 56/59 ACMG genes ranged between 0.3% to 2.34% in five studies (13,19,21,22,41), while Rego et al reported an 8.5% difference (9).…”

“…These 20 articles had over 76,749 participants (mean of 3837.45, median 789, range 70-50,726). Five studies performed the analysis of incidental findings in healthy cohorts (9)(10)(11)(12)(13). Five studies included both healthy and disease cohorts (14)(15)(16)(17)(18).…”

“…Four studies included a mixed cohort from pediatric and adult participants (15,18,19,21). One study used WGS to generate the data (16), five studies used WGS or WES (12,13,(22)(23)(24), and the rest of the included studies used WES only. Different ancestries were found in the 20 included studies.…”

“…The majority of included articles in our study (90%) restricted the report of selected variants to those, which were heterozygous for autosomal dominant conditions and homozygous, compound heterozygous, and hemizygous for autosomal recessive conditions, in accordance with the ACMG recommendation of reporting the medically actionable variants (1, 2). Only two papers calculated the frequency of identified pathogenic and likely pathogenic variants for all participants, including those with carrier status, who are heterozygous for autosomal recessive conditions (13,43).…”