Peer Review Report For: Identification of Pathogenic PKHD1 Variants in Infants with Autosomal Recessive Polycystic Kidney Disease from the Dhofar Region, Oman [version 1; peer review: 1 approved]

Background Autosomal recessive polycystic kidney disease (ARPKD) is a rare, inherited disorder primarily affecting the kidneys and liver. Disease-causing variants in PKHD1 lead to a disruption of the encoded protein fibrocystin/polyductin. This study aims to identify disease causing variants in PKHD1 in families from the Dhofar region of Oman. Methods We conducted a case series of six families with antenatal diagnoses of ARPKD and postnatal deaths. Genetic testing was performed on neonates using Sanger sequencing and next-generation sequencing (NGS) to detect variants in PKHD1. In silico analysis of mutational consequences was performed. Results 5 distinct homozygous variants in the PKHD1 gene were identified, including three pathogenic frameshift variants (c.6111_6112delTT, c.7011dupT and c.9550dupT), a nonsense variant (c.340C>T) and a homozygous deletion spanning exons 58-60 of the PKHD1. These alleles have not been reported in previous studies. In silico modelling identified pathogenic alleles, predicted to lead to either truncated protein products or nonsense-mediated decay. Discussion Our findings identify disease causing PKHD1 variants in this genetically distinct Dhofar population, potentially due to factors such as geographical isolation, consanguinity, and founder effects. The identification of previously undescribed variants underscores the need for regional genetic studies in understanding ARPKD and its genotype-phenotype correlations. Conclusion This study reveals distinct PKHD1 disease-causing variants in the Dhofar region of Oman, contributing to the broader genetic understanding of ARPKD. These findings highlight the value of region-specific genetic research in identifying new disease causing variants.