Objective:In some patients with adenomatous polyposis,an identifiable pathogenic variant of known associated genes cannot be found.Researchers have studied this for decades;however,few new genes have been identified.M...Objective:In some patients with adenomatous polyposis,an identifiable pathogenic variant of known associated genes cannot be found.Researchers have studied this for decades;however,few new genes have been identified.Methods:Adenomatous polyposis coli(APC)negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification.Then,whole-exome sequencing(WES)was used to determine candidate genes harboring pathogenic variants.Functional experiments were performed to explore their effects.Subsequently,using Sanger sequencing,we found other polyposis patients carrying variants of the DUOX2 gene,encoding dual oxidase 2,and analyzed them.Results:From 88 patients with suspected familial adenomatous polyposis,25 unrelated APC negative polyposis patients were identified.Based on the WES results of 3 patients and 2 healthy relatives from a family,the germline nonsense variant(c.1588 A>T;p.K530 X)of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis.During functional experiments,we observed that the truncated protein,h Duox2 K530,was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant,causing abnormal cell proliferation through endoplasmic reticulum(ER)retention.In addition,we found two unrelated APC negative patients carrying DUOX2 missense variants(c.3329 G>A,p.R1110 Q;c.4027 C>T,p.L1343 F).Given the results of the in silico analysis,these two missense variants might exert a negative influence on the function of h Duox2.Conclusions:To our knowledge,this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis.With an autosomal dominant inheritance,it causes ER retention,inducing an unfolded protein response.展开更多
BACKGROUND Congenital hepatic fibrosis(CHF)is a rare autosomal recessive disorder characterized by variable degrees of periportal fibrosis and malformation of bile ducts.CHF is generally accompanied by a variety of co...BACKGROUND Congenital hepatic fibrosis(CHF)is a rare autosomal recessive disorder characterized by variable degrees of periportal fibrosis and malformation of bile ducts.CHF is generally accompanied by a variety of conditions or syndromes with other organ involvement.CASE SUMMARY We report a 5-year-4-month-old Chinese boy with congenital hypothyroidism(CH)diagnosed with CHF.The patient was diagnosed with CH by a newborn screening test and has since been taking levothyroxine.He has developed normally without neurocognitive deficits.Abnormal liver function was observed in the patient at the age of 4 years and 11 mo,and elevated levels of liver function indices were persistent for 5 mo.Radiological imaging indicated hepatosplenomegaly without narrowing of the portal vein but dilated splenic vein.A liver biopsy confirmed the pathological features of CHF.Genetic testing revealed two novel homozygous mutations,namely,c.2141-3T>C variant in PKHD1 related to CHF and c.2921G>A(p.R974H)in DUOX2 related to CH.The patient was treated with compound glycyrrhizin tablet,ursodeoxycholic acid,and levothyroxine after diagnosis.The patient achieved a favorable clinical outcome during a follow-up period of over 2 years.CONCLUSION Herein,we report the first case of a Chinese boy with comorbidity of CHF and CH,carrying both PKHD1 gene and DUOX2 gene novel mutations.Liver biopsy and genetic testing should be considered for the diagnosis of coexistent liver disease in CH patients with unexplained abnormal liver function.展开更多
基金supported by the National Key R&D Program of China(Grant No.2017YFC0908200)the National Natural Science Foundation of China(Grant Nos.81872481 and 81902956)。
文摘Objective:In some patients with adenomatous polyposis,an identifiable pathogenic variant of known associated genes cannot be found.Researchers have studied this for decades;however,few new genes have been identified.Methods:Adenomatous polyposis coli(APC)negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification.Then,whole-exome sequencing(WES)was used to determine candidate genes harboring pathogenic variants.Functional experiments were performed to explore their effects.Subsequently,using Sanger sequencing,we found other polyposis patients carrying variants of the DUOX2 gene,encoding dual oxidase 2,and analyzed them.Results:From 88 patients with suspected familial adenomatous polyposis,25 unrelated APC negative polyposis patients were identified.Based on the WES results of 3 patients and 2 healthy relatives from a family,the germline nonsense variant(c.1588 A>T;p.K530 X)of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis.During functional experiments,we observed that the truncated protein,h Duox2 K530,was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant,causing abnormal cell proliferation through endoplasmic reticulum(ER)retention.In addition,we found two unrelated APC negative patients carrying DUOX2 missense variants(c.3329 G>A,p.R1110 Q;c.4027 C>T,p.L1343 F).Given the results of the in silico analysis,these two missense variants might exert a negative influence on the function of h Duox2.Conclusions:To our knowledge,this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis.With an autosomal dominant inheritance,it causes ER retention,inducing an unfolded protein response.
基金Supported by National Natural Science Foundation of China,No.81870373Shanghai Hospital Development Center New Frontier Technology Joint Research Project,No.SHDC12017115and 2019 Shanghai“Innovative Action Plan of Science and Technology”Animal Research Project Guide,No.19140904301.
文摘BACKGROUND Congenital hepatic fibrosis(CHF)is a rare autosomal recessive disorder characterized by variable degrees of periportal fibrosis and malformation of bile ducts.CHF is generally accompanied by a variety of conditions or syndromes with other organ involvement.CASE SUMMARY We report a 5-year-4-month-old Chinese boy with congenital hypothyroidism(CH)diagnosed with CHF.The patient was diagnosed with CH by a newborn screening test and has since been taking levothyroxine.He has developed normally without neurocognitive deficits.Abnormal liver function was observed in the patient at the age of 4 years and 11 mo,and elevated levels of liver function indices were persistent for 5 mo.Radiological imaging indicated hepatosplenomegaly without narrowing of the portal vein but dilated splenic vein.A liver biopsy confirmed the pathological features of CHF.Genetic testing revealed two novel homozygous mutations,namely,c.2141-3T>C variant in PKHD1 related to CHF and c.2921G>A(p.R974H)in DUOX2 related to CH.The patient was treated with compound glycyrrhizin tablet,ursodeoxycholic acid,and levothyroxine after diagnosis.The patient achieved a favorable clinical outcome during a follow-up period of over 2 years.CONCLUSION Herein,we report the first case of a Chinese boy with comorbidity of CHF and CH,carrying both PKHD1 gene and DUOX2 gene novel mutations.Liver biopsy and genetic testing should be considered for the diagnosis of coexistent liver disease in CH patients with unexplained abnormal liver function.
