False positive cell free DNA screening for microdeletions due to non‐pathogenic copy number variants

Abstract

What's Already Known about This Topic? Aneuploidy screening using cell free DNA (cfDNA) has recently been expanded to include selected microdeletions. However, validation has been limited, and the real‐world positive‐predictive value is unknown. What Does This Study Add? Here we describe three cases of false positive cfDNA microdeletions because of small, non‐pathogenic copy number variants near the region of interest. These findings elucidate one mechanism of false‐positive results with this screening test and suggest that additional validation is necessary before wider use in clinical practice.

The benefits and limitations of cell‐free DNA screening for 22q11.2 deletion syndrome

“…Another recent publication described two false positive cases for the 22q11.2 deletion because of small, non-pathogenic copy number variants near the critical 22q11.2 deletion region. 72 The authors noted that if these alternate copy number variants are determined to routinely lead to positive testing, this mechanism would strongly limit the theoretical positive predictive value of cell-free DNA screening for microdeletions and microduplications. This experience may provide an indication for parental testing to determine the mechanism causing a false positive result and be useful information in testing future pregnancies.…”

Current controversies in prenatal diagnosis 2: Cell‐free DNA prenatal screening should be used to identify all chromosome abnormalities

“…Most studies report very small numbers of abnormal cases, as might be expected given the rarity of these conditions, but it must be remembered that the false‐positive rate will be cumulative. In some studies, the false‐positive rate is high partly due to detection of maternal rearrangements (Table ). Other contributors include confined placental mosaicism, as in a recent case of a 22q11.2 deletion that was a discordant positive cfDNA test shown to be due to CPM .…”

Genetics of Mental Retardation

“…По-видимому, существенный вклад в структуру ум-ственной отсталости вносят микроделеционные синдромы, однако точно оценить их значение пока не удается. С одной стороны, методы их диагностики остаются дорогими и данных недостаточно для оцен-ки частоты, с другой стороны, микроделеции нередко встречаются в норме [18,19], что затрудняет опре-деление их этиологической роли в умственной от-сталости. Примеры хорошо изученных синдромов, связанных в части случаев с делецией фрагмента хро-мосомы 15, -синдром Прадера-Вилли с частотой 1:10 000-30 000 новорожденных [20] и синдром Ан-гельмана с частотой 1:10 000-20 000 новорожденных [21].…”