一个两次多囊肾胎儿孕育史家系的临床分析及遗传咨询
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摘要
目的:对一个有过两次多囊肾胎儿孕育史的家系进行临床表型及遗传学病因分析,为再次妊娠提供遗传咨询。方法:对该家系相关成员行肝肾超声筛查;用高通量测序技术对先证者及其配偶行包括多囊肾在内的63个遗传性肾病基因筛查,筛选与该病发生可能相关的基因,应用PCR和一代测序对先证者及其相关亲属进行验证。结果与结论:超声筛查提示先证者及其母亲为双肾多发囊肿,其弟双侧肾脏为多囊肾改变,其姐双肾未见囊肿,先证者配偶超声未见异常。高通量测序筛查提示先证者携带与成人型多囊肾相关的PKD1基因c. 10678G> A(p. G3560R)杂合突变,其母及其姐均携带该突变,而其弟未检测到该突变。先证者的妻子经高通量测序筛查未发现与多囊肾相关的基因突变。PKD1基因c. 10678G> A(p. G3560R)杂合突变位点为先证者家庭胎儿或成人患者致病突变的可能性小。建议先证者妻子在孕期详细行胎儿肾脏超声检查以降低该家庭的生育风险。
Aim: To analyze the clinical phenotype and genetic etiology of a family which had a history of two fetuses manifesting polycystic kidney,so as to provide genetic counseling to guide further pregnancy. Methods: Ultrasound scanning of liver and kidney was performed for the proband(the father of the two fetuses) and the other relevant family members.Next generation sequencing(NGS) including 63 genes involved with polycystic kidney was performed for the proband and his wife. For the suspicious genes screened by NGS,PCR and Sanger sequencing were applied to verify the mutation among the proband and the other relevant family members. Results and Conclusion: Ultrasound screening showed that the proband and his mother had multiple cysts in bilateral kidneys. The younger brother of the proband was shown with polycystic kidney. No renal cysts were found in the spouse or sister of the proband. A heterozygous mutation c. 10678 G > A(p. G3560 R) of PKD1 gene was detected in the proband,his mother and sister,but not in his younger brother. No genetic mutations were detected by NGS in the spouse of the proband. Combined with the clinic findings and the genetic results,c. 10678 G > A(p. G3560 R) of PKD1 gene may not be the disease-causing mutation in this family. The family of the proband is recommended to get more careful ultrasound scanning during next pregnancy to prevent the birth of child with renal abnormality.
Aim: To analyze the clinical phenotype and genetic etiology of a family which had a history of two fetuses manifesting polycystic kidney,so as to provide genetic counseling to guide further pregnancy. Methods: Ultrasound scanning of liver and kidney was performed for the proband(the father of the two fetuses) and the other relevant family members.Next generation sequencing(NGS) including 63 genes involved with polycystic kidney was performed for the proband and his wife. For the suspicious genes screened by NGS,PCR and Sanger sequencing were applied to verify the mutation among the proband and the other relevant family members. Results and Conclusion: Ultrasound screening showed that the proband and his mother had multiple cysts in bilateral kidneys. The younger brother of the proband was shown with polycystic kidney. No renal cysts were found in the spouse or sister of the proband. A heterozygous mutation c. 10678 G > A(p. G3560 R) of PKD1 gene was detected in the proband,his mother and sister,but not in his younger brother. No genetic mutations were detected by NGS in the spouse of the proband. Combined with the clinic findings and the genetic results,c. 10678 G > A(p. G3560 R) of PKD1 gene may not be the disease-causing mutation in this family. The family of the proband is recommended to get more careful ultrasound scanning during next pregnancy to prevent the birth of child with renal abnormality.
引文
[1]BERGMANN C,VON BOTHMER J,ORTIZ BRCHLE N,et al.Mutations in multiple PKD genes may explain early and severe polycystic kidney disease[J].J Am Soc Nephrol.2011,22(11):20472
[2]BSCHER R1,BSCHER AK,WEBER S,et al.Clinical manifestations of autosomal recessive polycystic kidney disease(ARPKD):kidney-related and non-kidney-related phenotypes[J].Pediatr Nephrol,2014,29(10):1915
[3]SIMMS RJ.Autosomal dominant polycystic kidney disease[J].BMJ,2016,352:i679
[4]MENEZES LF,ONUCHIC LF.Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease[J].Braz J Med Biol Res,2006,39(12):1537
[5]BERGMANN C.ARPKD and early manifestations of ADP-KD:the original polycystic kidney disease and phenocopies[J].Pediatr Nephrol,2015,30(1):15
[6]ZERRES K,MCHER G,BACHNER L,et al.Mapping of the gene for autosomal recessive polycystic kidney disease(ARPKD)to chromosome 6p21-cen[J].Nat Genet,1994,7(3):429
[7]GUAY-WOODFORD LM,MUECHER G,HOPKINS SD,et al.The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6p21.1-p12:implications for genetic counseling[J].Am J Hum Genet,1995,56(5):1101
[8]LU H,GALEANO MCR,OTT E,et al.Mutations in DZ-IP1L,which encodes a ciliary-transition-zone protein,cause autosomal recessive polycystic kidney disease[J].Nat Genet,2017,49(7):1025
[9]ONG AC,DEVUYST O,KNEBELMANN B,et al.Autosomal dominant polycystic kidney disease:the changing face of clinical management[J].Lancet,2015,385(9981):1993
[10]BAE KT,SUN H,LEE JG,et al.Novel methodology to evaluate renal cysts in polycystic kidney disease[J].Am JNephrol,2014,39(3):210
[11]TORRES VE.Water for ADPKD?Probably,yes[J].JAm Soc Nephrol,2006,17(8):2089
[12]GRANTHAM JJ.Clinical practice.Autosomal dominant polycystic kidney disease[J].N Engl J Med,2008,359(14):1477
[13]ROSSETTI S,HARRIS PC.Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystickidney disease[J].J Am Soc Nephrol,2007,18(5):1374
[14]ROSSETTI S,CONSUGAR MB,CHAPMAN AB,et al.Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease[J].J Am Soc Nephrol,2007,18(7):2143
[15]BERGMANN C.Genetics of autosomal recessive polycystic kidney disease and its differential diagnoses[J].Front Pediatr,2018,5:221
[16]BERGMANN C,SENDEREK J,WINDELEN E,et al.Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease(ARP-KD)[J].Kidney Int,2005,67(3):829
[17]ROY S,DILLON MJ,TROMPETER RS,et al.Autosomal recessive polycystic kidney disease:long-term outcome of neonatal survivors[J].Pediatr Nephrol,1997,11(3):302
[18]TANEDA S,HONDA K,AOKI A,et al.An autopsy case of clinically un-diagnosed autosomal recessive polycystic kidney disease in 77-year-old male[J].Pathol Int,2012,62(12):811
[19]CARRERA P,CALZAVARA S,MAGISTRONI R,et al.Deciphering variability of PKD1 and PKD2 in an Italian cohort of 643 patients with autosomal dominant polycystic kidney disease(ADPKD)[J].Sci Rep,2016,6:30850
[20]TSUCHIYA K,KOMEDA M,TAKAHASHI M,et al.Mutational analysis within the 3'region of the PKD1 gene in Japanese families[J].Mutat Res,2001,458(3/4):77
[2]BSCHER R1,BSCHER AK,WEBER S,et al.Clinical manifestations of autosomal recessive polycystic kidney disease(ARPKD):kidney-related and non-kidney-related phenotypes[J].Pediatr Nephrol,2014,29(10):1915
[3]SIMMS RJ.Autosomal dominant polycystic kidney disease[J].BMJ,2016,352:i679
[4]MENEZES LF,ONUCHIC LF.Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease[J].Braz J Med Biol Res,2006,39(12):1537
[5]BERGMANN C.ARPKD and early manifestations of ADP-KD:the original polycystic kidney disease and phenocopies[J].Pediatr Nephrol,2015,30(1):15
[6]ZERRES K,MCHER G,BACHNER L,et al.Mapping of the gene for autosomal recessive polycystic kidney disease(ARPKD)to chromosome 6p21-cen[J].Nat Genet,1994,7(3):429
[7]GUAY-WOODFORD LM,MUECHER G,HOPKINS SD,et al.The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6p21.1-p12:implications for genetic counseling[J].Am J Hum Genet,1995,56(5):1101
[8]LU H,GALEANO MCR,OTT E,et al.Mutations in DZ-IP1L,which encodes a ciliary-transition-zone protein,cause autosomal recessive polycystic kidney disease[J].Nat Genet,2017,49(7):1025
[9]ONG AC,DEVUYST O,KNEBELMANN B,et al.Autosomal dominant polycystic kidney disease:the changing face of clinical management[J].Lancet,2015,385(9981):1993
[10]BAE KT,SUN H,LEE JG,et al.Novel methodology to evaluate renal cysts in polycystic kidney disease[J].Am JNephrol,2014,39(3):210
[11]TORRES VE.Water for ADPKD?Probably,yes[J].JAm Soc Nephrol,2006,17(8):2089
[12]GRANTHAM JJ.Clinical practice.Autosomal dominant polycystic kidney disease[J].N Engl J Med,2008,359(14):1477
[13]ROSSETTI S,HARRIS PC.Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystickidney disease[J].J Am Soc Nephrol,2007,18(5):1374
[14]ROSSETTI S,CONSUGAR MB,CHAPMAN AB,et al.Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease[J].J Am Soc Nephrol,2007,18(7):2143
[15]BERGMANN C.Genetics of autosomal recessive polycystic kidney disease and its differential diagnoses[J].Front Pediatr,2018,5:221
[16]BERGMANN C,SENDEREK J,WINDELEN E,et al.Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease(ARP-KD)[J].Kidney Int,2005,67(3):829
[17]ROY S,DILLON MJ,TROMPETER RS,et al.Autosomal recessive polycystic kidney disease:long-term outcome of neonatal survivors[J].Pediatr Nephrol,1997,11(3):302
[18]TANEDA S,HONDA K,AOKI A,et al.An autopsy case of clinically un-diagnosed autosomal recessive polycystic kidney disease in 77-year-old male[J].Pathol Int,2012,62(12):811
[19]CARRERA P,CALZAVARA S,MAGISTRONI R,et al.Deciphering variability of PKD1 and PKD2 in an Italian cohort of 643 patients with autosomal dominant polycystic kidney disease(ADPKD)[J].Sci Rep,2016,6:30850
[20]TSUCHIYA K,KOMEDA M,TAKAHASHI M,et al.Mutational analysis within the 3'region of the PKD1 gene in Japanese families[J].Mutat Res,2001,458(3/4):77