Prenatal Phenotypes And Gene Diagnoses Of Bardet-Biedl Syndrome Fetuses

BackgroundBardet-Biedl syndrome（BBS）is an autosomal recessive inherited ciliopathy,involving multiple organs and systems.At present,there is no effective treatment for BBS,and it has a high rate of death and disability.BBS is rare and highly clinical and genetic heterogeneous,making early and prenatal diagnoses difficult.The development of gene diagnosis technology provides the possibility for prenatal diagnosis of BBS,but at present,the understanding of BBS intrauterine phenotype is limited,and prenatal gene diagnosis is rare in the absence of family history.Therefore,it is of great significance to explore the intrauterine phenotype,pathogenic genes and variations spectrum of BBS for its prenatal and postnatal diagnosis,clinical management,family genetic counseling and risk assessment of recurrence in offspring.ObjectiveGenetic analysis was performed on the suspected BBS cases with intrauterine phenotypes of "polydactyly" and "renal enlargement/echo enhancement/cyst" to confirm the genetic diagnosis,and provide reference for family genetic counseling.Furthermore,with literature review,the intrauterine phenotype and molecular genetic characteristics of BBS were summarized and analyzed in order to deepen the clinical understanding of this syndrome and lay a foundation for the prenatal diagnosis of BBS.Methods（1）A total of 24 suspected BBS fetuses were collected from the genetic clinic of Shenzhen Maternal and Child Health Hospital affiliated to Southern Medical University Hospital from May 2015 to October 2020.The clinical data of the patients was analyzed and the candidate pathogenic genes were screened by high-throughput sequencing and bioinformatic analysis,and the candidate pathogenic gene variations were verified by Sanger sequencing.（2）Literature reviewLiteratures included in China National Knowledge Infrastructure,Wanfang database,and Pubmed database from the establishment of the database to December 2020 were searched,and those related to the intrauterine/prenatal phenotype of fetus diagnosed with BBS by genetic tests were selected.And the clinical data and gene mutation data of these BBS fetuses were analyzed.Results（1）Of the 24 cases,11 cases declined/failed to obtain samples for the genetic testing,and the remaining 13 cases have performed high-throughput sequencing,of which 4 cases found no pathogenic or likely pathogenic mutation,4 cases were detected BBS gene biallelic variations,5 cases found other genetic diseases.The candidate pathogenic variants of BBS in the above four cases were verified by Sanger sequencing.Case 1 carried paternally inherited c.718G>A（p.Gly240Ser）variation and maternally inherited c.497C>A（p.Ala166Asp）variation in BBS7 gene.Case 2 carried paternally inherited c.1002delT（p.Asn335Ilefs*47）variation and maternally inherited c.728G>A（p.Cys243Tyr）variation in BBS7 gene.Case 3 carried a homozygous variant of c.534+1 G>T in BBS2 gene,and his father and mother were heterozygotes of this variation.While one maternally inherited variation c.127G>C（p.Gly43Arg）and one paternally inherited heterozygous variation c.636₆38delinsGG（p.Phe212Leufs*22）were identified in BBS9 gene of case 4.Given the imaging findings and the whole testing results,all four cases were diagnosed with BBS.（2）Literature reviewThe data of 67 BBS fetuses were analyzed.Approximately 85%（57/67）cases had polydactyly,94%（63/67）had renal abnormalities,and 81%（54/67）had both polydactyly and renal abnormalities.Conclusions1.The intrauterine phenotypes of BBS fetuses include polydactyly and bilateral renal enlargement/hyperechogenicity/cyst during the second and third trimester.However,given that those prenatal phenotypes are lack of specificity,further genetic tests such as whole exome sequencing should be used to confirm the diagnosis of suspected BBS cases.2.Up to now,the genetic changes of some BBS patients are still unknown,and further research and exploration should be made to find new pathogenic genes and loci of BBS for these cases.3.For BBS cases with neither family history nor prenatal phenotype,it is necessary to explore appropriate prenatal and postnatal screening methods for early molecular diagnosis.