Population screening for 15q11-q13 duplications: corroboration of the difference in impact between maternally and paternally inherited alleles

Abstract

Maternally inherited 15q11-q13 duplications are generally found to cause more severe neurodevelopmental anomalies compared to paternally inherited duplications. However, this assessment is mainly inferred from the study of patient populations, causing an ascertainment bias towards patients at the more severe end of the phenotypic spectrum. Here, we analyze the low coverage genome-wide cell-free DNA sequencing data obtained from pregnant women during non-invasive prenatal screening (NIPS). We detect 23 15q11-q13 duplications in 333,187 pregnant women (0.0069%), with an approximately equal distribution between maternal and paternal duplications. Maternally inherited duplications are always associated with a clinical phenotype (ranging from learning difficulties to intellectual impairment, epilepsy and psychiatric disorders), while paternal duplications are normal or associated with milder phenotypes (mild learning difficulties and dyslexia). This data corroborates the difference in impact between paternally and maternally inherited 15q11-q13 duplications, contributing to the improvement of genetic counselling. We recommend reporting 15q11-q13 duplications identified during genome-wide NIPS with appropriate genetic counselling for these pregnant women in the interest of both mothers and future children.

Fig. 1. Genomic representation of the 15q11-q13 region.

The 23 duplications detected with NIPS are sorted by parental origin and size and are shown in blue (maternal origin), light blue (paternal origin) and grey (unknown origin). The Prader-Willi/Angelman critical region is shown in red. At the bottom is a track of segmental duplication regions, with the different breakpoints (BP1-BP5) shown in orange.