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) .