SAT-334 GENETIC TESTING OF FAMILIES WITH VERY EARLY ONSET POLYCYSTIC KIDNEY DISEASE REVEALS THE FUNCTIONAL SIGNIFICANCE OF HYPOMORPHIC VARIANTS

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is generally an adult onset disorder; however rare very early onset (VEO) cases under the age of 2 years are reported and have a high recurrence risk in subsequent pregnancies. Elucidation of the underlying mechanism causing the early onset phenotype has significant benefits for genetic and reproductive counselling. We performed an audit of all ADPKD diagnostic referrals with age of onset less than 2 years referred for diagnostic genetic testing of PKD1 and PKD2 from 2010-2018. Testing was performed by long-range PCR with Sanger sequencing of all coding exons and/or next-generation sequencing (from 2016 onwards) and MLPA. A total of 28 cases with reported age of disease onset under 2 years were identified. 5 patients with a clinical history not suggestive of ADPKD and no mutation detected in PKD1 and PKD2 were subsequently excluded. Of the remaining 23 patients, 15 (65%) had at least 2 variants detected, including one likely hypomorphic variant; 4 (22%) had one pathogenic PKD1 mutation and 3 (13%) had no mutation detected in PKD1 or PKD2. Parental analysis from 12 families confirmed biallelic inheritance in 9 (75%) cases and 4 (33%) cases with a de novo mutation. Bilineal inheritance of PKD1 and PKD2 variants was found in 2 cases and biallelic PKD2 mutations in 1 case. Of the 15 patients with multiple variants, 13 had a likely or definitely pathogenic mutation as well as a likely hypomorphic variant; whilst 2 patients had 2 likely hypomorphic variants confirmed in trans. 10 (43%) cases had no previous family history of ADPKD. This study highlights a high incidence of hypomorphic variants inherited in trans with a pathogenic mutation or another hypomorphic variant in children with a VEO phenotype. The previously reported and experimentally validated p.(Arg3277Cys) hypomorphic PKD1 variant was detected in 3 families. The minor allele frequency of the hypomorphic variants detected ranged from 0-0.2% which is higher than expected for a disease-causing variant. These variants require careful consideration in the context of early onset disease and parental segregation analysis to determine phase. Our study also demonstrates a high incidence of de novo mutations and high incidence of cases with no previous family history. A model of reduced gene dosage during embryonic kidney maturation is the simplest molecular mechanism underlying the VEO phenotype.