Gene pathogenicity analysis.
PKHD1 gene c.830delC(p.aSN2768fs) is a splicing mutation, which leads to premature termination of protein translation and changes in protein function (PVS1).Not found in the Genome Aggregation Database (GnomAD) (PM2), the mutation was preliminarily assessed as likely pathogenic (PVS1+PM2) according to ACMG guidelines. However, the duplicated exon 57-60 of PKHD1 gene constituted a complex heterozygous variation with c. 830delC (p.Asn2768fs).It has been reported that children with autosomal recessive polycystic kidney type 4 were detected with exon 33-35 and exon 45-46 duplicates of thePKHD1 gene.6, 7
JAG1 gene c. 2078_2079delGT (p.Cys693FS) heterozygous mutation, which is splicing mutation, will advance the translation termination codon, resulting in the termination of protein translation, causing protein function change (PVS1);It was not found in the Exome Aggregation Consortium (ExAC) and Genome Aggregation Database(GnomAD) (PM2).However, it was rated as P (PP5) in the Clinvar database, and therefore as a pathogenic variant (PVS1+PM2+PP5) according to ACMG guidelines.
DYNC2H1 gene c.557G>T and c.7643T>C complex heterozygous variation.c.557G>T(p.Gly186Val) was a missense mutation, which was not found in the Genome Aggregation Database(GnomAD) (PM2).It can form a compound heterozygous variation with c. 7643T>C(p.Phe2548Ser) (PM3).According to the ACMG guidelines, this mutation is a uncertain significant mutation (PM2+PM3).c.7643T>C(p.Phe2548Ser) heterozygous variant is a missense variant detected in patients with short rib multidigit (toe) syndrome (PS1),not found in the Genome Aggregation Database(GnomAD) and Reference Human Thousand Genomes (1000G) (PM2),However, this mutation was rated as P in Clinvar and DM (PP5) in the Human Mutation Database. According to the ACMG guidelines, the mutation was suspected to be pathogenic (PS1+PM2+PM3).C.8190G>T and c. 8621delC inDYNC2H1 gene, c.8190G>T(p.Leu2730Phe) is a missense mutation. The mutation is located in the Dynein heavy chain, p-loop containing D4 domain (PM1),Very low frequency (PM2) in the Human Genome Mutation Frequency Database (GnomAD),This mutation and c.8621delC(p.Leu2876fs *15) constituted a compound heterozygous mutation (PM3), which was rated as LP in Clinvar database (PP5).According to ACMG guidelines, the mutation is suspected to be pathogenic (PM1+PM2+PM3+PP5).c.8621delC(p.Leu2876fs *15) is a frameshift mutation that causes changes in the reading frame and changes in protein function (PVS1), which is not found in the Genome Aggregation Database(GnomAD) (PM2).This mutation and the heterozygous variation of c.8190G>T(p.Leu2730phe) constituted a compound heterozygous variation (PM3), which was suspected to be pathogenic variation according to ACMG guidelines(PVS1+PM1+PM2) .