TY - JOUR
T1 - A Deep Intronic PKHD1 Variant Identified by SpliceAI in a Deceased Neonate With Autosomal Recessive Polycystic Kidney Disease
AU - Richter, Felix
AU - Rutherford, Kayleigh D.
AU - Cooke, Anisha J.
AU - Meshkati, Malorie
AU - Eddy-Abrams, Vanessa
AU - Greene, Daniel
AU - Kosowsky, Jordana
AU - Park, Yeaji
AU - Aggarwal, Surabhi
AU - Burke, Rebecca J.
AU - Chang, Weili
AU - Connors, Jillian
AU - Giannone, Peter J.
AU - Hays, Thomas
AU - Khattar, Divya
AU - Polak, Mark
AU - Senaldi, Liana
AU - Smith-Raska, Matthew
AU - Sridhar, Shanthy
AU - Steiner, Laurie
AU - Swanson, Jonathan R.
AU - Tauber, Kate A.
AU - Barbosa, Mafalda
AU - Guttmann, Katherine F.
AU - Turro, Ernest
N1 - Publisher Copyright:
© 2024 National Kidney Foundation, Inc.
PY - 2024/6
Y1 - 2024/6
N2 - 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 147 bp 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.
AB - 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 147 bp 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.
UR - http://www.scopus.com/inward/record.url?scp=85184773092&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85184773092&partnerID=8YFLogxK
U2 - 10.1053/j.ajkd.2023.12.011
DO - 10.1053/j.ajkd.2023.12.011
M3 - Article
C2 - 38211685
AN - SCOPUS:85184773092
SN - 0272-6386
VL - 83
SP - 829
EP - 833
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 6
ER -