标题:
Genetic mutational testing for Chinese children with familial haematuria with biopsy-proven FSGS
讲者:
李永珍
单位:
中南大学湘雅二医院
来源:
中华医学会第二十一次全国儿科学术大会2016年10月20-23日
播放:
568
论文摘要:
Backgrounds and objectives Focal segmental glomerulosclerosis(FSGS) is a pathologic lesion rather than a disease,and the etiology is diverse.FSGS can be caused by genetic factors and non-genetic factors. The reason FSGS is considered a podocyte disease because most of FSGS-proven patients is due to defects in the podocyte structure or function. However,FSGS can not only be caused by podocytes-related genes,but also by other genes such as Collagen IV-related genes.Patients who carry COL4A3 or COL4A4 mutation usually exhibit Alport Syndrome(AS) ,TBMN or familial heamaturia(FH).Recent studies revealed that long-time persistent microscopic haematuriais can lead to FSGS. We described a family where affected individuals presented with familial hematuria with FSGS-proven , or chronic kidney disease. Renal biopsies were unhelpful and failed to show glomerular or basement membrane defects consistent with an inherited glomerulopathy,and therefore we pursued a possible underlying genetic cause for a unifying diagnosis.
Methods We used genomic DNA of the siblings affected by familial heamaturia with biopsy-proven focal segmental glomerulosclerosis (FSGS) and their father to screen for 15 genes mutations associated with FSGS(NPHS1, NPHS2, CD2AP, PLCE1, ACTN4, TRPC6 ,INF2, WT1,LMX1B,LAMB2, LAMB3,GLA, ITGB4,SCARB2,COQ2,PDSS2, TNRL1,SMARCAL1)using MALDI-TOF(matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) technology.Then Whole exome sequencing (WES) was performed in the two probands to find whether there were other known or unknown genes mutations segregated with disease.
Results Using MassArray technology, we identified a TRNL1 missense homozygous mutation(m.3290T>C) in the probands who had been diagnosed with FH and manifested as FSGS on biopsy. In addition,a COL4A4 missense mutation c.4195A>T (p.M1399L) in heterozygous pattern was identified using WES. None of these variants were detected in their father.
Conclusions We have identified a mutation in TRNL1(m.3290T>C) which was the first reported variant associated with FSGS probably. The COL4A4(c.4195A>T) may co-segregated with FSGS. we suggest screening for COL4A mutations in familial FSGS patients.Genetic investigations of families with similar clinical phenotypes should be a priority for nephrologists.The combination of Massarray technology and Whole exome sequencing can improve the detection rate of genetic mutation with a high level accurate.