To explore clinical phenotypes and genotypes of PKHD1 gene variants in children with autosomal recessive polycystic kidney disease (ARPKD) who were diagnosed in neonate, infant and teenage age.

Three children (probands) (case 1: 25-day-old boy, case 2: 4-year-old girl, case 3: 13-year-old girl) diagnosed with ARPKD who visited Xi′an Children′s Hospital due to " fetal kidney enlargement, requiring further examination" " dysuria with fever for 2 days" and " frequent urination with dysuria", respectively from January 1, 2021 to June 30, 2022 were selected as research subjects. Clinical phenotypes of PKHD1 gene variants and laboratory findings of three children were analyzed by retrospective method. Whole exome sequencing (WES) and Sanger sequencing were carried out to detect potential pathogenic variants and family verification. According to the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the ACMG guideline), pathogenicity of PKHD1 gene variants was comprehensively assessed. The procedure followed in this study was in accordance with the regulations of the Ethics Committee of Xi′an Children′s Hospital, and was reviewed and approved by the Ethics Committee (Approval No. 20220059).

①Clinical phenotypes of PKHD1 gene variants and auxiliary examination results of 3 children: all three children had bilateral renal volume enlargement with multiple cysts in both kidneys, and had no abnormal liver function and renal function, and no hematuria and proteinuria in urine routine. Case 2 and 3 children had liver fibrosis combined with intrahepatic bile duct dilatation, and case 1 had hypertension. ②PKHD1 gene detection of three children and their family members: case 1 had compound heterozygous variants of c. 11223T>G(p.Y3741*) and c. 4682G>A (p.C1561Y), which inherited from his mother and father, respectively. Case 2 had c. 9007T>C(p.S3003P) and c. 5935G>A(p.G1979R) compound heterozygous variants, which inherited from her mother and father, respectively, and her two twin younger brothers both carried heterozygous variant of c. 5935G>A. Case 3 was found with compound heterozygous variants of c. 11542G>C(p.V3848L) and c. 5935G>A(p.G1979R), which inherited from her mother and father, respectively, and her elder sister also had same compound heterozygous variants at the above locus, and her younger brother carried heterozygous variant of c. 9007T>C. ③Pathogenicity analysis of the above 5 PKHD1 gene variants according to ACMG guideline: c.4682G>A(p.G1979R) and c. 5935G>A(p.G1979R) were variant of uncertain significance and pathogenic variant, respectively. While c. 11223T>G(p.Y3741*), c. 9007T>C(p.S3003P) and c.11542G>C(p.V3848L) were nonsense variant, missense variant and missense variant, respectively, and were judged to be likely pathogenic variant, likely pathogenic variant and variant of uncertain significance, respectively according to ACMG guideline.

The three children in this research were diagnosed as ARPKD caused by PKHD1 gene variants through genetic testing. Considering the variable clinical phenotype of this disease, which has similar clinical phenotype with other cystic kidney diseases, early genetic testing of children suspected of this disease is of great significance for genetic counseling and the prognosis of children with this disease.