A Presumed Synonymous Mutation of PKD2 Caused Autosomal Dominant Polycystic Kidney Disease in a Chinese Family

Objective:Autosomal dominant polycystic kidney disease(ADPKD)is mainly caused by the pathogenic mutation of PKD1 or PKD2 gene and usually affects bilateral kidneys.Synonymous mutations are generally assumed to be neutral as they do not alter amino acids.Herein,we described an extremely rare ADPKD child caused by a heterozygous synonymous mutation of PKD2 gene accompanied by massive proteinuria and congenital solitary kidney.Methods:Clinical characteristics of the patients were summarized.Whole-exome sequencing was performed to screen the disease-causing gene mutation,and reverse transcription polymerase chain reaction(RT-PCR)and Sanger sequencing were applied to analyze the impact of the identified mutation on gene transcription and splicing.Results:Polycystic changes were found in the solitary kidney of a girl initially presented with nephrotic-range proteinuria.Thereafter her mother and 2 other family members were diagnosed to be ADPKD.Whole-exome sequencing of the proband identified a heterozygous synonymous mutation(c.1716G>A,p.Lys572=)located in the splicing site of exon 7 in PKD2 gene,which was co-segregated with the PKD phenotype in the family.RT-PCR and direct sequencing of amplified products revealed that this heterozygous synonymous mutation led to exon7 skipping in PKD2 gene.Conclusion:We reported an extremely rare child case of ADPKD2 in combination with solitary kidney and nephrotic-range proteinuria,and firstly confirmed the pathogenicity of a heterozygous synonymous mutation(c.1716G>A)in PKD2 gene.The results indicate that synonymous mutations should not be excluded from disease-causing if they are located in splicing site of an exon.

Delayed-onset adenosine deaminase deficiency with a novel synonymous mutation and a case series from China

Background Adenosine deaminase(ADA)is a key enzyme in the purine salvage pathway.Genetic defects of the ADA gene can cause a subtype of severe combined immunodeficiency.To date,few Chinese cases have been reported.Methods We retrospectively reviewed the medical records of patients diagnosed with ADA deficiency in Beijing Children's Hospital and summarized the previously published ADA deficiency cases from China in the literature.Results Nine patients were identified with two novel mutations(W272X and Q202=).Early-onset infection,thymic abnor-malities and failure to thrive were the most common manifestations of Chinese ADA-deficient patients.The ADA genotype has a major effect on the clinical phenotype.Notably,a novel synonymous mutation(c.606G>A,p.Q202=)was identified in a delayed-onset patient,which affected pre-mRNA splicing leading to a frameshift and premature truncation of the protein.Furthermore,the patient showed γδT cells expansion with an increased effect or phenotype,which may be associated with the delayed onset of disease.In addition,we reported cerebral aneurysm and intracranial artery stenosis for the first time in ADA deficiency.Five patients died with a median age of four months,while two patients received stem cell transplantation and are alive.Conclusions This study described the first case series of Chinese ADA-deficient patients.Early-onset infection,thymic abnormalities and failure to thrive were the most common manifestations in our patients.We identified a synonymous muta-tion that affected pre-mRNA splicing in the ADA gene,which had never been reported in ADA deficiency.Furthermore,we reported cerebral aneurysm in a delayed-onset patient for the first time.Further study is warranted to investigate the underlying mechanisms.

Identification of genome-wide nucleotide sites associated with mammalian virulence in influenza A viruses

The virulence of influenza viruses is a complex multigenic trait.Previous studies about the virulence determinants of influenza viruses mainly focused on amino acid sites,ignoring the influence of nucleotide mutations.In this study,we collected>200 viral strains from 21 subtypes of influenza A viruses with virulence in mammals and obtained over 100 mammalian virulence-related nucleotide sites across the genome by computational analysis.Fifty of these nucleotide sites only experienced synonymous mutations.Experiments showed that synonymous mutations in three high-scoring nucleotide sites,i.e.,PB1–2031,PB1–633,and PB1–720,enhanced the pathogenicity of the influenza A(H1N1)viruses in mice.Besides,machine-learning models with accepted accuracy for predicting mammalian virulence of influenza A viruses were built.Overall,this study highlighted the importance of nucleotide mutations,especially synonymous mutations in viral virulence,and provided rapid methods for evaluating the virulence of influenza A viruses.It could be helpful for early warning of newly emerging influenza A viruses.