Multicystic dysplastic kidney (MCDK) is one of the most common fetal malformations, but its etiology remains unclear. Identification of the molecular etiology could provide a basis for prenatal diagnosis, consultation, and prognosis evaluation for MCDK fetuses. We used chromosome microarray analysis (CMA) and whole-exome sequencing (WES) to conduct genetic tests on MCDK fetuses and explore their genetic etiology. A total of 108 MCDK fetuses with or without other extrarenal abnormalities were selected. Karyotype analysis of 108 MCDK fetuses showed an abnormal karyotype in 4 (3.7%, 4/108) of the fetuses. However, CMA detected 15 abnormal copy number variations (CNVs) (14 pathogenic CNVs, and one variant of unknown significance [VUS] CNVs), in addition to four cases that were consistent with the results of karyotype analysis. Out of the 14 pathogenic CNVs cases, three were of 17q12 microdeletion, two of 22q11.21 microdeletion, 22q11.21 microduplication uniparental disomy (UPD), and one case of 4q31.3q32.2 microdeletion, 7q11.23 microduplication, 15q11.2 microdeletion, 16p11.2 microdeletion, and 17p12 microdeletion. Of the 89 MCDK fetuses with normal karyotype analysis and CMA, 15 were tested by WES. Two (13.3%, 2/15) fetuses were identified by WES as Bardet-Biedl syndrome (BBS) 1 and BBS2. Combined application of CMA-WES to detect MCDK fetuses can significantly improve the detection rate of genetic etiology, providing a basis for consultation, and prognosis evaluation.
MoralıoğluSCelayirACBosnalıOPektaşOZBulutIK. Single center experience in patients with unilateral multicystic dysplastic kidney.J Pediatr Urol2014;10:763–8
2.
AslamMWatsonAR, Trent Anglia MCDK Study Group. Multicystic dysplastic kidney: long term outcomes.Arch Dis Child2006;91:820–3
3.
GordonACThomasDFArthurRJIrvingHC. Multicystic dysplastic kidney: is nephrectomy still appropriate.J Urol1988;140:1231–4
4.
TokaHRTokaOHaririANguyenHT. Congenital anomalies of kidney and urinary tract.Semin Nephrol2010;30:374–86
5.
SchönfelderEMKnüppelTTasicVMiljkovicPKonradMWühlEAntignacCBakkalogluASchaeferFWeberS, ESCAPE Trial Group. Mutations in Uroplakin IIIA are a rare cause of renal hypodysplasia in humans.Am J Kidney Dis2006;47:1004–12
6.
IatropoulosPDainaEMeleCMarantaRRemuzziGNorisM. Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation.Pediatr Nephrol2012;27:1989–93
7.
WeberSMoriniereVKnüppelTCharbitMDusekJGhiggeriGMJankauskienéAMirSMontiniGPeco-AnticAWühlEZurowskaAMMehlsOAntignacCSchaeferFSalomonR. Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study.J Am Soc Nephrol2006;17:2864–70
8.
ZhangYZhongMZhengD. Chromosomal mosaicism detected by karyotyping and chromosomal microarray analysis in prenatal diagnosis.J Cell Mol Med2021;25:358–66
9.
BradyPDVermeeschJR. Genomic microarrays: a technology overview.Prenat Diagn2012;32:336–43
10.
SrebniakMIVan OpstalDJoostenMDiderichKEde VriesFARiedijkSKnapenMFGoATGovaertsLCGaljaardRJ. Whole-genome array as a first-line cytogenetic test in prenatal diagnosis.Ultrasound Obstet Gynecol2015;45:363–72
11.
Melanie Manning Louanne Hudgins . Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities.Genet Med2010;12:742–5
12.
GahlWAMarkelloTCToroCFajardoKFSincanMGillFCarlson-DonohoeHGropmanAPiersonTMGolasGWolfeLGrodenCGodfreyRNehrebeckyMWahlCLandisDMYangSMadeoAMullikinJCBoerkoelCFTifftCJAdamsD. The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases.Genet Med2012;14:51–9
13.
WouKDeBieICarrollJBrockJADouglas WilsonR. Fetal exome sequencing on the horizon.J Obstet Gynaecol Can2019;41:64–7
14.
RabbaniBTekinMMahdiehN. The promise of whole-exome sequencing in medical genetics.J Hum Genet2014;59:5–15
15.
RiggsERAndersenEFCherryAMKantarciSKearneyHPatelA. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).Genet Med2020;22:245–57
16.
RichardsSAzizNBaleSBickDDasSGastier-FosterJ. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med2015;17:405–24
17.
StaeblerMDonnerCRegemorterNVDuprezLAvniF. Should determination of the karyotype be systematic for all malformations detected by obstetrical ultrasound?Prenat Diagn2010;25:567–73
18.
HsuPYYuCHLinKChengYCChangCHChangFM. Prenatal diagnosis of fetal multicystic dysplastic kidney in the era of three-dimensional ultrasound: 10-year experience.Taiwan J Obstet Gynecol2012;51:596–602
19.
JelinASagaserKLawsonCForsterKRBlakemoreK. Chromosomal microarray analysis results from pregnancies with various ultrasonographic anomalies.Obstet Gynecol2019;133:827–8
20.
DixitAPatelCHarrisonRJarvisJHultonSSmithNYatesKSilcockLMcMullanDJSuriM. 17q12 microdeletion syndrome: three patients illustrating the phenotypic spectrum.Am J Med Genet A2012;158A:2317–21
21.
DecramerSParantOBeaufilsSClauinSGuillouCKesslerSAzizaJBandinFSchanstraJPBellanné-ChantelotC. Anomalies of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys.J Am Soc Nephrol2007;18:923–33
22.
HendrixNWClemensMCanavanTPSurtiURajkovicA. Prenatally diagnosed 17q12 microdeletion syndrome with a novel association with congenital diaphragmatic hernia Fetal.Diagn Ther2012;31:129–33
23.
HukriedeNATsangTEHabasRKhooPLSteinerKWeeksDLTamPPDawidIB. Conserved requirement of Lim1 function for cell movements during gastrulation.Dev Cell2003;4:83–94
24.
Lopez-RiveraELiuYPVerbitskyMSanna-CherchiS. Genetic drivers of kidney defects in the DiGeorge syndrome.N Engl J Med2017;376:742–54
25.
YuTLiJLiNLiuRDingYChangGChenYShenYWangXWangJ. Obesity and developmental delay in a patient with uniparental disomy of chromosome 2.Int J Obes2016;40:1935–41
EarhartBAWilliamsMEZamoraIRandolphLMVotava-SmithJKMarcySN. Phenotype of 7q11.23 duplication: a family clinical series.Am J Med Genet A2017;173:114–9
28.
ZhouBZhangCZhengLWangZChenXFengXZhangQHaoSWeiLGuWHuiL. Case report: a novel De Novo Missense mutation of the GRIA2 gene in a Chinese case of neurodevelopmental disorder with language impairment.Front Genet2021;12:794766
29.
RamkumarSMoonJGolczakMvon LintigJ. LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis from β-carotene.J Lipid Res2021;62:100055
30.
GohESBanwellBStavropoulosDJShagoMYoonG. Mosaic microdeletion of 17p11.2-p12 and duplication of 17q22-q24 in a girl with Smith-Magenis phenotype and peripheral neuropathy.Am J Med Genet A2014;164A:748–52
31.
XieHLiuFZhangYChenQShangguanSGaoZWuNWangJCuiXWangLChenX. Neurodevelopmental trajectory and modifiers of 16p11.2 microdeletion: a follow-up study of four Chinese children carriers.Mol Genet Genomic Med2020;8:e1485
32.
SilvaAIKirovGKendallKMBracher-SmithMWilkinsonLSHallJ. Analysis of diffusion tensor imaging data from the UK Biobank confirms dosage effect of 15q11.2 copy number variation on white matter and shows association with cognition.Biol Psychiatry2021;90:307–16
33.
HorikawaYIwasakiNHaraMFurutaHHinokioYCockburnBN. Mutation in hepatocyte nuclear factor|[ndash]|1|[beta]| gene (TCF2) associated with MODY.Nature Genetics1997;17:384–5
34.
SanyanusinPSchimmentiLAMcNoeLAWardTAPierpontMESullivanMJDobynsWBEcclesMR. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux.Nat Genet1995;9:358–64
35.
HarshmanLABrophyPD. PAX2 in human kidney malformations and disease.Pediatr Nephrol2012;27:1265–75
36.
SaisawatPKohlSHilgerACHwangDYYung GeeHDworschakGCTasicVPennimpedeTNatarajanSSperryEMatassaDSStajićNBogdanovicRde BlaauwIMarcelisCLWijersCHBartelsESchmiedekeESchmidtDMärzheuserSGrasshoff-DerrSHolland-CunzSLudwigMNöthenMMDraakenMBrosensEHeijHTibboelDHerrmannBGSolomonBDde KleinAvan RooijIAEspositoFReutterHMHildebrandtF. Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association.Kidney Int2014;85:1310–7
37.
VivanteAHwangDYKohlSChenJShrilSSchulzJvan der VenADaoukGSolimanNAKumarASSenguttuvanPKehindeEOTasicVHildebrandtF. Exome sequencing discerns syndromes in patients from consanguineous families with congenital anomalies of the kidneys and urinary tract.J Am Soc Nephrol2017;28:69–75
38.
HumbertCSilbermannFMorarBJeanpierreC. Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans.Am J Hum Genet2014;94:288294
39.
MaryLChennenKStoetzelCAntinMLeuvreyANourissonEAlanio-DettonEAntalMCAttié-BitachTBouvagnetPBouvierRBuenerdAClémensonADevismeLGasserBGilbert-DussardierBGuimiotFKhau Van KienPLeroyBLogetPMartinovicJPelluardFPerezMJPetitFPinsonLRooryck-ThamboCPochODollfusHSchaeferEMullerJ. Bardet-Biedl syndrome: antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.Clin Genet2019;95:384–97
40.
EspositoGTestaFZacchiaMCrispoAADi IorioVCapolongoG. Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants.BMC Med Genet2017;18:10
