The etiologies of newborn deaths in neonatal intensive care units usually
remain unknown, even after genetic testing. Whole-genome sequencing,
combined with artificial intelligence-based methods for predicting the
effects of non-coding variants, provide an avenue for resolving these
deaths. Using one such method, SpliceAI, we identified a maternally
inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans
with a pathogenic missense variant (p.Thr36Met), in a newborn who died of
autosomal recessive polycystic kidney disease at age 2 days. We validated
the deep intronic variant’s impact in maternal urine-derived cells
expressing PKHD1. Reverse transcription polymerase chain reaction followed
by Sanger sequencing showed that the variant causes inclusion of 147bp of
the canonical intron between exons 29 and 30 of PKHD1 into the mRNA,
including a premature stop codon. Allele-specific expression analysis at a
heterozygous site in the mother showed that the mutant allele completely
suppresses canonical splicing. In an unrelated healthy control, there was
no evidence of transcripts including the novel splice junction. We returned
a diagnostic report to the parents, who underwent in vitro embryo
selection.