SAT-436 CLINICAL AND GENETIC CHARACTERISTICS OF AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (ARPKD) PATIENTS FROM OMAN AND PKHD1 FOUNDER MUTATIONS

Abstract

The Omani population has a high prevalence of rare genetic disorders, and their study provides unique clinical and genetic insights. Autosomal recessive polycystic kidney disease (ARPKD) is one of the leading causes of kidney and liver-associated morbidity and mortality in the country. We aimed to describe the clinical and genetic profile of ARPKD patients from Oman. A group of 75 patients and relatives (40 males and 35 females) from apparently 33 unrelated families, who were referred to the National Genetic Centre in Oman between January 2015 and December 2018, were studied. This included 41 patients with a clinical diagnosis of ARPKD, their parents (n=24) and siblings or relatives (n=10). Genetic analysis of PKHD1 was performed through next generation sequencing (NGS) and Sanger sequencing. A clinical diagnosis was made in 5 patients prenatally, 24 were diagnosed during the infancy period (0-1 year), nine during early childhood (2-8 years) and 3 at later ages (9-13 years). The main clinical features of patients included hypertension, hepatic fibrosis and splenomegaly. 25 patients had documented chronic renal failure at a median age of 3 years. 24 out of 33 families had a family history suggesting an autosomal recessive pattern of inheritance, and there was known consanguinity in 22 families (67%). A molecular genetic diagnosis of ARPKD with biallelic PKHD1 mutations was confirmed in 30 families (n= 38 patients), giving a detection rate of 91%. Three families remained genetically unsolved. In total, only four different PKHD1 missense pathogenic mutations were identified: c.107C>T; (Thr36Met), c.406A>G; (Thr136Ala), c.4870C>T; (Arg1624Trp) and c.9370C>T; (His3124Tyr) located in exons 3, 6, 32 and 58, respectively. The c.406A>G; (Thr136Ala) is a novel missense mutation that was detected homozygously in one family and heterozygously with c.107C>T; (Thr36Met) allele in 5 other families. Overall, the most commonly detected pathogenic allele was c.107C>T; (Thr36Met), which was seen in 24 families. All four PKHD1 mutations were detected in patients from all governorates of the country except, Musandam, Al Wusta and Dhofar. Molecular genetic screening of suspected ARPKD cases produces a highly yield of genetic diagnosis. The four PKHD1 missense mutations may suggest common founder alleles in Omani population and allow cost effective targeted PCR analysis of these specific alleles to be a useful diagnostic tool.