P371
EVALUATION OF CLINICAL MOLECULAR GENETIC TESTING FOR ADPKD IN A
MULTIDISCIPLINARY CLINIC
Sandford, R1, Robinson, C1, Daboo, L1, Karet, F1,2
Department of Medical Genetics and Division of Renal Medicine, Addenbrooke’s
Hospital, Cambridge
Autosomal dominant polycystic kidney disease (ADPKD) is the commonest inherited renal
disease, affecting up to 6-8% of patients with end-stage renal failure (ESRF) and >1:1000 of the
population. ADPKD is associated with mutations in PKD1 or PKD2. Genic effects are strong,
mutations in PKD1 commonly being associated with more severe disease and earlier onset of
ESRF. However, allelic affects are weak, with poor genotype-phenotype correlations that have
little clinical predictive value.
The role of genetic testing in the clinic environment has not been established except for a few
specific indications such as prenatal diagnosis. PKD2 mutation testing is available in North
America and Europe by linkage analysis, direct sequencing and/or deletion/duplication analysis,
whilst PKD1 screening is limited mainly to linkage analysis. Mutation analysis for PKD2,
together with linkage analysis for PKD1/PKD2, has now been established in a single UK centre
and national approval gained for direct clinical testing.
We evaluated PKD2 testing in a cohort of 144 ADPKD probands in a single centre. All were
referred to a specialist renal genetics clinic. ADPKD patients on dialysis, or in low-clearance or
transplant clinics, were not included in this study.
Direct sequencing of the PKD2 gene revealed a likely pathogenic mutation in 28 patients (19%).
Of these, 72% were truncations/frameshifts/splice junction mutations, and the remainder were
missense alterations not present on dbSNP. Mutation carriers had a mean age at diagnosis of
41y (range 18-68) vs. 38y (5-71) in those with no mutation. 71% vs. 84% were treated for
hypertension. 25% vs. 36% gave no family history of ADPKD, while 50% vs. 57% had no
family history of ESRF (all NS).
Where there was a family history of ESRF, it occurred approximately 10y later in the PKD2
group compared to those lacking mutations (64.4y vs. 54.3y; p = 0.0001). A family history of
ESRF before the age of 45 rendered identification of a PKD2 genotype very unlikely (p =
0.037), suggesting that a larger range of patients is worthy of PKD2 screening than has
previously been considered.
Conclusions: PKD2 gene testing has a clinically useful detection rate and can effectively be
introduced into routine clinical care. It should be offered to any PKD patient whose renal
function is relatively well preserved for age, where there is no family history of early ESRF, and
to at-risk family members when a mutation has been identified. This information will allow
earlier diagnosis than current ultrasound-based evaluation, accelerating care pathways and
providing important information for family genetic counselling.