The present and future of whole-exome sequencing in studying and treating human reproductive disorders
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摘要
The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.
The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.
The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.
引文
ACMG,2012.Points to consider in the clinical application of genomic sequencing.Genet.Med.14,759e761.
Alazami,A.M.,Awad,S.M.,Coskun,S.,Al-Hassan,S.,Hijazi,H.,Abdulwahab,F.M.,Poizat,C.,Alkuraya,F.S.,2015.TLE6 mutation causes the earliest known human embryonic lethality.Genome Biol.16,240.
ASRM,2013.Definitions of infertility and recurrent pregnancy loss:a committee opinion.Fertil.Steril.99,63.
Asadollahi,R.,Oneda,B.,Joset,P.,Azzarello-Burri,S.,Bartholdi,D.,Steindl,K.,Vincent,M.,Cobilanschi,J.,Sticht,H.,Baldinger,R.,Reissmann,R.,Sudholt,I.,Thiel,C.T.,Ekici,A.B.,Reis,A.,Bijlsma,E.K.,Andrieux,J.,Dieux,A.,FitzPatrick,D.,Ritter,S.,Baumer,A.,Latal,B.,Plecko,B.,Jenni,O.G.,Rauch,A.,2014.The clinical significance of small copy number variants in neurodevelopmental disorders.J.Med.Genet.51,677e688.
Asselta,R.,Spena,S.,Duga,S.,Tenchini,M.L.,2007.Molecular genetics of quantitative fibrinogen disorders.Cardiovasc.Hematol.Agents Med.Chem.5,163e173.
Bamshad,M.J.,Shendure,J.A.,Valle,D.,Hamosh,A.,Lupski,J.R.,Gibbs,R.A.,Boerwinkle,E.,Lifton,R.P.,Gerstein,M.,Gunel,M.,Mane,S.,Nickerson,D.A.,2012.The Centers for Mendelian Genomics:a new large-scale initiative to identify the genes underlying rare Mendelian conditions.Am.J.Med.Genet.158A,1523e1525.
Bao,R.,Huang,L.,Andrade,J.,Tan,W.,Kibbe,W.A.,Jiang,H.,Feng,G.,2014.Review of current methods,applications,and data management for the bioinformatics analysis of whole exome sequencing.Cancer Inform.13,67e82.
Bhuiyan,Z.A.,Momenah,T.S.,Gong,Q.,Amin,A.S.,Ghamdi,S.A.,Carvalho,J.S.,Homfray,T.,Mannens,M.M.,Zhou,Z.,Wilde,A.A.,2008.Recurrent intrauterine fetal loss due to near absence of HERG:clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation.Heart Rhythm.5,553e561.
Boycott,K.M.,Rath,A.,Chong,J.X.,Hartley,T.,Alkuraya,F.S.,Baynam,G.,Brookes,A.J.,Brudno,M.,Carracedo,A.,den Dunnen,J.T.,Dyke,S.,Estivill,X.,Goldblatt,J.,Gonthier,C.,Groft,S.C.,Gut,I.,Hamosh,A.,Hieter,P.,Hohn,S.,Hurles,M.E.,Kaufmann,P.,Knoppers,B.M.,Krischer,J.P.,Macek,M.J.,Matthijs,G.,Olry,A.,Parker,S.,Paschall,J.,Philippakis,A.A.,Rehm,H.L.,Robinson,P.N.,Sham,P.C.,Stefanov,R.,Taruscio,D.,Unni,D.,Vanstone,M.R.,Zhang,F.,Brunner,H.,Bamshad,M.J.,Lochmuller,H.,2017.International cooperation to enable the diagnosis of all rare genetic diseases.Am.J.Hum.Genet.100,695e705.
Boycott,K.M.,Vanstone,M.R.,Bulman,D.E.,MacKenzie,A.E.,2013.Rare-disease genetics in the era of next-generation sequencing:discovery to translation.Nat.Rev.Genet.14,681e691.
Boyd,P.A.,Tondi,F.,Hicks,N.R.,Chamberlain,P.F.,2004.Autopsy after termination of pregnancy for fetal anomaly:retrospective cohort study.BMJ 328,137.
Brown,T.L.,Meloche,T.M.,2016.Exome sequencing a review of new strategies for rare genomic disease research.Genomics 108,109e114.
Carss,K.J.,Hillman,S.C.,Parthiban,V.,McMullan,D.J.,Maher,E.R.,Kilby,M.D.,Hurles,M.E.,2014.Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound.Hum.Mol.Genet.23,3269e3277.
CDC,2008.Update on overall prevalence of major birth defects-Atlanta,Georgia,1978-2005.MMWR Morb.Mortal.Wkly.Rep.57,1e5.
Choi,M.,Scholl,U.I.,Ji,W.,Liu,T.,Tikhonova,I.R.,Zumbo,P.,Nayir,A.,Bakkaloglu,A.,Ozen,S.,Sanjad,S.,Nelson-Williams,C.,Farhi,A.,Mane,S.,Lifton,R.P.,2009.Genetic diagnosis by whole exome capture and massively parallel DNAsequencing.Proc.Natl.Acad.Sci.U.S.A.106,19096e19101.
Chong,J.X.,Buckingham,K.J.,Jhangiani,S.N.,Boehm,C.,Sobreira,N.,Smith,J.D.,Harrell,T.M.,McMillin,M.J.,Wiszniewski,W.,Gambin,T.,Coban,A.Z.,Doheny,K.,Scott,A.F.,Avramopoulos,D.,Chakravarti,A.,Hoover-Fong,J.,Mathews,D.,Witmer,P.D.,Ling,H.,Hetrick,K.,Watkins,L.,Patterson,K.E.,Reinier,F.,Blue,E.,Muzny,D.,Kircher,M.,Bilguvar,K.,Lopez-Giraldez,F.,Sutton,V.R.,Tabor,H.K.,Leal,S.M.,Gunel,M.,Mane,S.,Gibbs,R.A.,Boerwinkle,E.,Hamosh,A.,Shendure,J.,Lupski,J.R.,Lifton,R.P.,Valle,D.,Nickerson,D.A.,Bamshad,M.J.,2015.The genetic basis of Mendelian phenotypes:discoveries,challenges,and opportunities.Am.J.Hum.Genet.97,199e215.
Cobourne,M.T.,2004.The complex genetics of cleft lip and palate.Eur.J.Orthod.26,7e16.
Dai,L.,Zhu,J.,Mao,M.,Li,Y.,Deng,Y.,Wang,Y.,Liang,J.,Tang,L.,Wang,H.,Kilfoy,B.A.,Zheng,T.,Zhang,Y.,2010.Time trends in oral clefts in Chinese newborns:data from the Chinese National Birth Defects Monitoring Network.Birth Defects Res.A Clin.Mol.Teratol.88,41e47.
D'Amours,G.,Kibar,Z.,Mathonnet,G.,Fetni,R.,Tihy,F.,Desilets,V.,Nizard,S.,Michaud,J.L.,Lemyre,E.,2012.Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype.Clin.Genet.81,128e141.
Dickinson,M.E.,Flenniken,A.M.,Ji,X.,Teboul,L.,Wong,M.D.,White,J.K.,Meehan,T.F.,Weninger,W.J.,Westerberg,H.,Adissu,H.,Baker,C.N.,Bower,L.,Brown,J.M.,Caddle,L.B.,Chiani,F.,Clary,D.,Cleak,J.,Daly,M.J.,Denegre,J.M.,Doe,B.,Dolan,M.E.,Edie,S.M.,Fuchs,H.,Gailus-Durner,V.,Galli,A.,Gambadoro,A.,Gallegos,J.,Guo,S.,Horner,N.R.,Hsu,C.W.,Johnson,S.J.,Kalaga,S.,Keith,L.C.,Lanoue,L.,Lawson,T.N.,Lek,M.,Mark,M.,Marschall,S.,Mason,J.,McElwee,M.L.,Newbigging,S.,Nutter,L.M.,Peterson,K.A.,RamirezSolis,R.,Rowland,D.J.,Ryder,E.,Samocha,K.E.,Seavitt,J.R.,Selloum,M.,SzokeKovacs,Z.,Tamura,M.,Trainor,A.G.,Tudose,I.,Wakana,S.,Warren,J.,Wendling,O.,West,D.B.,Wong,L.,Yoshiki,A.,MacArthur,D.G.,TocchiniValentini,G.P.,Gao,X.,Flicek,P.,Bradley,A.,Skarnes,W.C.,Justice,M.J.,Parkinson,H.E.,Moore,M.,Wells,S.,Braun,R.E.,Svenson,K.L.,de Angelis,M.H.,Herault,Y.,Mohun,T.,Mallon,A.M.,Henkelman,R.M.,Brown,S.D.,Adams,D.J.,Lloyd,K.C.,McKerlie,C.,Beaudet,A.L.,Bucan,M.,Murray,S.A.,2016.Highthroughput discovery of novel developmental phenotypes.Nature 537,508e514.
Dinwiddie,D.L.,Smith,L.D.,Miller,N.A.,Atherton,A.M.,Farrow,E.G.,Strenk,M.E.,Soden,S.E.,Saunders,C.J.,Kingsmore,S.F.,2013.Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome.Genomics 102,148e156.
Dixon,M.J.,Marazita,M.L.,Beaty,T.H.,Murray,J.C.,2011.Cleft lip and palate:understanding genetic and environmental influences.Nat.Rev.Genet.12,167e178.
Drury,S.,Boustred,C.,Tekman,M.,Stanescu,H.,Kleta,R.,Lench,N.,Chitty,L.S.,Scott,R.H.,2014.A novel homozygous ERCC5 truncating mutation in a family with prenatal arthrogryposis-further evidence of genotype-phenotype correlation.Am.J.Med.Genet.164A,1777e1783.
Drury,S.,Williams,H.,Trump,N.,Boustred,C.,Lench,N.,Scott,R.H.,Chitty,L.S.,2015.Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities.Prenat.Diagn.35,1010e1017.
Ellard,S.,Kivuva,E.,Turnpenny,P.,Stals,K.,Johnson,M.,Xie,W.,Caswell,R.,Lango,A.H.,2015.An exome sequencing strategy to diagnose lethal autosomal recessive disorders.Eur.J.Hum.Genet.23,401e404.
Falardeau,F.,Camurri,M.V.,Campeau,P.M.,2017.Genomic approaches to diagnose rare bone disorders.Bone 102,5e14.
Filges,I.,Friedman,J.M.,2015.Exome sequencing for gene discovery in lethal fetal disorders-harnessing the value of extreme phenotypes.Prenat.Diagn.35,1005e1009.
Filges,I.,Manokhina,I.,Penaherrera,M.S.,McFadden,D.E.,Louie,K.,Nosova,E.,Friedman,J.M.,Robinson,W.P.,2015.Recurrent triploidy due to a failure to complete maternal meiosis II:whole-exome sequencing reveals candidate variants.Mol.Hum.Reprod.21,339e346.
Filges,I.,Nosova,E.,Bruder,E.,Tercanli,S.,Townsend,K.,Gibson,W.T.,Rothlisberger,B.,Heinimann,K.,Hall,J.G.,Gregory-Evans,C.Y.,Wasserman,W.W.,Miny,P.,Friedman,J.M.,2014.Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype.Clin.Genet.86,220e228.
FitzPatrick,D.R.,et al.,2003.Identification of SATB2 as the cleft palate gene on2q32-q33.Hum.Mol.Genet.12,2491e2501.
Forlino,A.,Marini,J.C.,2016.Osteogenesis imperfecta.Lancet 387,1657e1671.
Geister,K.A.,Camper,S.A.,2015.Advances in skeletal dysplasia genetics.Annu.Rev.Genomics Hum.Genet.16,199e227.
Gelb,B.,Brueckner,M.,Chung,W.,Goldmuntz,E.,Kaltman,J.,Kaski,J.P.,Kim,R.,Kline,J.,Mercer-Rosa,L.,Porter,G.,Roberts,A.,Rosenberg,E.,Seiden,H.,Seidman,C.,Sleeper,L.,Tennstedt,S.,Kaltman,J.,Schramm,C.,Burns,K.,Pearson,G.,Rosenberg,E.,2013.The congenital heart disease genetic network study:rationale,design,and early results.Circ.Res.112,698e706.
Giannandrea,M.,Parks,W.C.,2014.Diverse functions of matrix metalloproteinases during fibrosis.Dis.Model Mech.7,193e203.
Guo,C.,Wang,Q.,Wang,Y.,Yang,L.,Luo,H.,Cao,X.F.,An,L.,Qiu,Y.,Du,M.,Ma,X.,Li,H.,Lu,C.,2017.Exome sequencing reveals novel IRXI mutation in congenital heart disease.Mol.Med.Rep.15,3193e3197.
Handyside,A.H.,Kontogianni,E.H.,Hardy,K.,Winston,R.M.,1990.Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification.Nature 344,768e770.
Hiersch,L.,Reches,A.,Simchoni,S.,Barel,D.,Greenberg,R.,Ben Sira,L.,Gustavo,M.,Y,Y.,2017.The added yield of whole exome sequencing in fetuses with suspected central nervous system abnormalities.In:Proceedings of 16th World Congress in Fetal Medicine,Ljubljana,Slovenia.
Hyde,K.J.,Schust,D.J.,2015.Genetic considerations in recurrent pregnancy loss.Cold Spring Harb.Perspect.Med.5,a023119.
Itoh,T.,Shirahama,S.,Nakashima,E.,Maeda,K.,Haga,N.,Kitoh,H.,Kosaki,R.,Ohashi,H.,Nishimura,G.,Ikegawa,S.,2006.Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population.Am.J.Med.Genet.140,1280e1284.
Jia,Z.,Fengbiao,M.,Wang,L.,Li,M.,Shi,Y.,Zhang,B.,Gao,G.,2017.Whole-exome sequencing identifies a de novo mutation in TRPM4 involved in pleiotropic ventricular septal defect.Int.J.Clin.Exp.Pathol.10,5092e5104.
Laurino,M.Y.,Bennett,R.L.,Saraiya,D.S.,Baumeister,L.,Doyle,D.L.,Leppig,K.,Pettersen,B.,Resta,R.,Shields,L.,Uhrich,S.,Varga,E.A.,Raskind,W.H.,2005.Genetic evaluation and counseling of couples with recurrent miscarriage:recommendations of the National Society of Genetic Counselors.J.Genet.Couns.14,165e181.
Lee,H.,Deignan,J.L.,Dorrani,N.,Strom,S.P.,Kantarci,S.,Quintero-Rivera,F.,Das,K.,Toy,T.,Harry,B.,Yourshaw,M.,Fox,M.,Fogel,B.L.,Martinez-Agosto,J.A.,Wong,D.A.,Chang,V.Y.,Shieh,P.B.,Palmer,C.G.,Dipple,K.M.,Grody,W.W.,Vilain,E.,Nelson,S.F.,2014.Clinical exome sequencing for genetic identification of rare Mendelian disorders.J.Am.Med.Assoc.312,1880e1887.
Lee,V.,Chow,J.,Yeung,W.,Ho,P.C.,2017.Preimplantation genetic diagnosis for monogenic diseases.Best Pract.Res.Clin.Obstet.Gynaecol.44,68e75.
Lewis,A.J.,Austin,E.,Knapp,R.,Vaiano,T.,Galbally,M.,2015.Perinatal maternal mental health,fetal programming and child development.Healthcare(Basel)3,1212e1227.
Li,T.C.,Makris,M.,Tomsu,M.,Tuckerman,E.,Laird,S.,2002.Recurrent miscarriage:aetiology,management and prognosis.Hum.Reprod.Update 8,463e481.
Lohmann,K.,Klein,C.,2014.Next generation sequencing and the future of genetic diagnosis.Neurotherapeutics 11,699e707.
Mademont-Soler,I.,Morales,C.,Soler,A.,Martinez-Crespo,J.M.,Shen,Y.,Margarit,E.,Clusellas,N.,Obon,M.,Wu,B.L.,Sanchez,A.,2013.Prenatal diagnosis of chromosomal abnormalities in fetuses with abnormal cardiac ultrasound findings:evaluation of chromosomal microarray-based analysis.Ultrasound Obstet.Gynecol.41,375e382.
Marazita,M.L.,Mooney,M.P.,2004 Apr.Current concepts in the embryology and genetics of cleft lip and cleft palate.Clin.Plast.Surg.31(2),125e140.
Marokakis,S.,Kasparian,N.A.,Kennedy,S.E.,2016.Prenatal counselling for congenital anomalies:a systematic review.Prenat.Diagn.36,662e671.
McCulley,D.J.1,Black,B.L.,2012.Transcription factor pathways and congenital heart disease.Curr.Top Dev.Biol.100,253e277.
McInerney-Leo,A.M.,Schmidts,M.,Cortes,C.R.,Leo,P.J.,Gener,B.,Courtney,A.D.,Gardiner,B.,Harris,J.A.,Lu,Y.,Marshall,M.,Scambler,P.J.,Beales,P.L.,Brown,M.A.,Zankl,A.,Mitchison,H.M.,Duncan,E.L.,Wicking,C.,2013.Shortrib polydactyly and Jeune syndromes are caused by mutations in WDR60.Am.J.Hum.Genet.93,515e523.
Mills,J.L.,2010.Malformations in infants of diabetic mothers.Teratology 25,385e394,1982.Birth Defects Res.A Clin.Mol.Teratol.88,769-778.
Mitchell,K.,O'Sullivan,J.,Missero,C.,Blair,E.,Richardson,R.,Anderson,B.,Antonini,D.,Murray,J.C.,Shanske,A.L.,Schutte,B.C.,Romano,R.A.,Sinha,S.,Bhaskar,S.S.,Black,G.C.,Dixon,J.,Dixon,M.J.,2012.Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus.Am.J.Hum.Genet.90,69e75.
Mossey,P.A.,Little,J.,Munger,R.G.,Dixon,M.J.,Shaw,W.C.,2009.Cleft lip and palate.Lancet 374,1773e1785.
Moyers,S.,Bailey,L.B.,2001.Fetal malformations and folate metabolism:review of recent evidence.Nutr.Rev.59,215e224.
Ng,S.B.,Buckingham,K.J.,Lee,C.,Bigham,A.W.,Tabor,H.K.,Dent,K.M.,Huff,C.D.,Shannon,P.T.,Jabs,E.W.,Nickerson,D.A.,Shendure,J.,Bamshad,M.J.,2010.Exome sequencing identifies the cause of a mendelian disorder.Nat.Genet.42,30e35.
Ng,S.B.,Turner,E.H.,Robertson,P.D.,Flygare,S.D.,Bigham,A.W.,Lee,C.,Shaffer,T.,Wong,M.,Bhattacharjee,A.,Eichler,E.E.,Bamshad,M.,Nickerson,D.A.,Shendure,J.,2009.Targeted capture and massively parallel sequencing of 12human exomes.Nature 461,272e276.
Ornoy,A.,Ergaz,Z.,2010.Alcohol abuse in pregnant women:effects on the fetus and newborn,mode of action and maternal treatment.Int.J.Environ.Res.Public Health 7,364e379.
Osoegawa,K.,Vessere,G.M.,Utami,K.H.,Mansilla,M.A.,Johnson,M.K.,Riley,B.M.,L'Heureux,J.,Pfundt,R.,Staaf,J.,van der Vliet,W.A.,Lidral,A.C.,Schoenmakers,E.F.,Borg,A.,Schutte,B.C.,Lammer,E.J.,Murray,J.C.,de Jong,P.J.,2008.Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridisation.J.Med.Genet.45,81e86.
Ottaviani,G.,Buja,L.M.,2017 Jul.Update on congenital heart disease and sudden infant/perinatal death:from history to future trends.J.Clin.Pathol.70(7),555e562.
Page,J.M.,Silver,R.M.,2016.Genetic causes of recurrent pregnancy loss.Clin.Obstet.Gynecol.59,498e508.
Pangalos,C.,Hagnefelt,B.,Lilakos,K.,Konialis,C.,2016.First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects.PeerJ 4e1955.
Pinto,A.M.,Imperatore,V.,Bianciardi,L.,Baldassarri,M.,Galluzzi,P.,Furini,S.,Centini,G.,Renieri,A.,Mari,F.,2017.Combined ultrasound and exome sequencing approach recognizes Opitz G/BBB syndrome in two malformed fetuses.Clin.Dysmorphol.26,18e25.
Putoux,A.,Thomas,S.,Coene,K.L.,Davis,E.E.,Alanay,Y.,Ogur,G.,Uz,E.,Buzas,D.,Gomes,C.,Patrier,S.,Bennett,C.L.,Elkhartoufi,N.,Frison,M.H.,Rigonnot,L.,Joye,N.,Pruvost,S.,Utine,G.E.,Boduroglu,K.,Nitschke,P.,Fertitta,L.,ThauvinRobinet,C.,Munnich,A.,Cormier-Daire,V.,Hennekam,R.,Colin,E.,Akarsu,N.A.,Bole-Feysot,C.,Cagnard,N.,Schmitt,A.,Goudin,N.,Lyonnet,S.,Encha-Razavi,F.,Siffroi,J.P.,Winey,M.,Katsanis,N.,Gonzales,M.,Vekemans,M.,Beales,P.L.,Attie-Bitach,T.,2011.KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes.Nat.Genet.43,601e606.
Qiao,Y.,Wen,J.,Tang,F.,Martell,S.,Shomer,N.,Leung,P.C.,Stephenson,M.D.,Rajcan-Separovic,E.,2016.Whole exome sequencing in recurrent early pregnancy loss.Mol.Hum.Reprod.22,364e372.
Quintero-Ronderos,P.,Mercier,E.,Fukuda,M.,Gonzalez,R.,Suarez,C.F.,Patarroyo,M.A.,Vaiman,D.,Gris,J.C.,Laissue,P.,2017.Novel genes and mutations in patients affected by recurrent pregnancy loss.PLoS One 12,e0186149.
Rabbani,B.,Tekin,M.,Mahdieh,N.,2014.The promise of whole-exome sequencing in medical genetics.J.Hum.Genet.59,5e15.
Ramos,E.I.,Bien-Willner,G.A.,Li,J.,Hughes,A.E.,Giacalone,J.,Chasnoff,S.,Kulkarni,S.,Parmacek,M.,Cole,F.S.,Druley,T.E.,2014.Genetic variation in MKL2 and decreased downstream PCTAIRE1 expression in extreme,fatal primary human microcephaly.Clin.Genet.85,423e432.
Retterer,K.,Juusola,J.,Cho,M.T.,Vitazka,P.,Millan,F.,Gibellini,F.,Vertino-Bell,A.,Smaoui,N.,Neidich,J.,Monaghan,K.G.,McKnight,D.,Bai,R.,Suchy,S.,Friedman,B.,Tahiliani,J.,Pineda-Alvarez,D.,Richard,G.,Brandt,T.,Haverfield,E.,Chung,W.K.,Bale,S.,2016.Clinical application of whole-exome sequencing across clinical indications.Genet.Med.18,696e704.
Romani,M.,Micalizzi,A.,Valente,E.M.,2013.Joubert syndrome:congenital cerebellar ataxia with the molar tooth.Lancet Neurol.12,894e905.
Roosing,S.,Romani,M.,Isrie,M.,Rosti,R.O.,Micalizzi,A.,Musaev,D.,Mazza,T.,AlGazali,L.,Altunoglu,U.,Boltshauser,E.,D'Arrigo,S.,De Keersmaecker,B.,Kayserili,H.,Brandenberger,S.,Kraoua,I.,Mark,P.R.,McKanna,T.,Van Keirsbilck,J.,Moerman,P.,Poretti,A.,Puri,R.,Van Esch,H.,Gleeson,J.G.,Valente,E.M.,2016.Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.J.Med.Genet.53,608e615.
Rossi,A.C.,Prefumo,F.,2013.Accuracy of ultrasonography at 11-14 weeks of gestation for detection of fetal structural anomalies:a systematic review.Obstet.Gynecol.122,1160e1167.
Sanders,A.A.,de Vrieze,E.,Alazami,A.M.,Alzahrani,F.,Malarkey,E.B.,Sorusch,N.,Tebbe,L.,Kuhns,S.,van Dam,T.J.,Alhashem,A.,Tabarki,B.,Lu,Q.,Lambacher,N.J.,Kennedy,J.E.,Bowie,R.V.,Hetterschijt,L.,van Beersum,S.,van Reeuwijk,J.,Boldt,K.,Kremer,H.,Kesterson,R.A.,Monies,D.,Abouelhoda,M.,Roepman,R.,Huynen,M.H.,Ueffing,M.,Russell,R.B.,Wolfrum,U.,Yoder,B.K.,van Wijk,E.,Alkuraya,F.S.,Blacque,O.E.,2015.KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome.Genome Biol.16,293.
Sawyer,S.L.,Hartley,T.,Dyment,D.A.,Beaulieu,C.L.,Schwartzentruber,J.,Smith,A.,Bedford,H.M.,Bernard,G.,Bernier,F.P.,Brais,B.,Bulman,D.E.,Warman,C.J.,Chitayat,D.,Deladoey,J.,Fernandez,B.A.,Frosk,P.,Geraghty,M.T.,Gerull,B.,Gibson,W.,Gow,R.M.,Graham,G.E.,Green,J.S.,Heon,E.,Horvath,G.,Innes,A.M.,Jabado,N.,Kim,R.H.,Koenekoop,R.K.,Khan,A.,Lehmann,O.J.,Mendoza-Londono,R.,Michaud,J.L.,Nikkel,S.M.,Penney,L.S.,Polychronakos,C.,Richer,J.,Rouleau,G.A.,Samuels,M.E.,Siu,V.M.,Suchowersky,O.,Tarnopolsky,M.A.,Yoon,G.,Zahir,F.R.,Majewski,J.,Boycott,K.M.,2016.Utility of whole-exome sequencing for those near the end of the diagnostic odyssey:time to address gaps in care.Clin.Genet.89,275 e284.
Scapoli,L.,Martinelli,M.,Arlotti,M.,Palmieri,A.,Masiero,E.,Pezzetti,F.,Carinci,F.,2008.Genes causing clefting syndromes as candidates for non-syndromic cleft lip with or without cleft palate:a family-based association study.Eur.J.Oral Sci.116,507e511.
Shamseldin,H.E.,Swaid,A.,Alkuraya,F.S.,2013.Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing.Genet.Med.15,307e309.
Shamseldin,H.E.,Kurdi,W.,Almusafri,F.,Alnemer,M.,Alkaff,A.,Babay,Z.,Alhashem,A.,Tulbah,M.,Alsahan,N.,Khan,R.,Sallout,B.,Al Mardawi,E.,Seidahmed,M.Z.,Meriki,N.,Alsaber,Y.,Qari,A.,Khalifa,O.,Eyaid,W.,Rahbeeni,Z.,Kurdi,A.,Hashem,M.,Alshidi,T.,Al-Obeid,E.,Abdulwahab,F.,Ibrahim,N.,Ewida,N.,El-Akouri,K.,Al Mulla,M.,Ben-Omran,T.,Pergande,M.,Cirak,S.,Al Tala,S.,Shaheen,R.,Faqeih,E.,Alkuraya,F.S.,2018 Apr.Molecular autopsy in maternal-fetal medicine.Genet.Med.20(4),420e427.
Shamseldin,H.E.,Tulbah,M.,Kurdi,W.,Nemer,M.,Alsahan,N.,Al,M.E.,Khalifa,O.,Hashem,A.,Kurdi,A.,Babay,Z.,Bubshait,D.K.,Ibrahim,N.,Abdulwahab,F.,Rahbeeni,Z.,Hashem,M.,Alkuraya,F.S.,2015.Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families.Genome Biol.16,116.
Sierra,S.,Stephenson,M.,2006.Genetics of recurrent pregnancy loss.Semin.Reprod.Med.24,17e24.
Silasi,M.,Cardenas,I.,Kwon,J.Y.,Racicot,K.,Aldo,P.,Mor,G.,2015.Viral infections during pregnancy.Am.J.Reprod.Immunol.73,199e213.
Soden,S.E.,Saunders,C.J.,Willig,L.K.,Farrow,E.G.,Smith,L.D.,Petrikin,J.E.,Le Pichon,J.B.,Miller,N.A.,Thiffault,I.,Dinwiddie,D.L.,Twist,G.,Noll,A.,Heese,B.A.,Zellmer,L.,Atherton,A.M.,Abdelmoity,A.T.,Safina,N.,Nyp,S.S.,Zuccarelli,B.,Larson,I.A.,Modrcin,A.,Herd,S.,Creed,M.,Ye,Z.,Yuan,X.,Brodsky,R.A.,Kingsmore,S.F.,2014.Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.Sci.Transl.Med.6,265ra168.
Stals,K.L.,Wakeling,M.,Baptista,J.,Caswell,R.,Parrish,A.,Rankin,J.,Tysoe,C.,Jones,G.,Gunning,A.C.,Lango,A.H.,Bradley,L.,Brady,A.F.,Carley,H.,Carmichael,J.,Castle,B.,Cilliers,D.,Cox,H.,Deshpande,C.,Dixit,A.,Eason,J.,Elmslie,F.,Fry,A.E.,Fryer,A.,Holder,M.,Homfray,T.,Kivuva,E.,McKay,V.,Newbury-Ecob,R.,Parker,M.,Savarirayan,R.,Searle,C.,Shannon,N.,Shears,D.,Smithson,S.,Thomas,E.,Turnpenny,P.D.,Varghese,V.,Vasudevan,P.,Wakeling,E.,Baple,E.L.,Ellard,S.,2018.Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.Prenat.Diagn.38,33e43.
Stark,Z.,Tan,T.Y.,Chong,B.,Brett,G.R.,Yap,P.,Walsh,M.,Yeung,A.,Peters,H.,Mordaunt,D.,Cowie,S.,Amor,D.J.,Savarirayan,R.,McGillivray,G.,Downie,L.,Ekert,P.G.,Theda,C.,James,P.A.,Yaplito-Lee,J.,Ryan,M.M.,Leventer,R.J.,Creed,E.,Macciocca,I.,Bell,K.M.,Oshlack,A.,Sadedin,S.,Georgeson,P.,Anderson,C.,Thorne,N.,Melbourne,G.H.A.,Gaff,C.,White,S.M.,2016.A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.Genet.Med.18,1090e1096.
Stern,H.J.,2014.Preimplantation genetic diagnosis:prenatal testing for embryos finally achieving its potential.J.Clin.Med.3,280e309.
Stranneheim,H.,Wedell,A.,2016.Exome and genome sequencing:a revolution for the discovery and diagnosis of monogenic disorders.J.Intern.Med.279,3e15.
Sumitha,E.,Jayandharan,G.R.,Arora,N.,Abraham,A.,David,S.,Devi,G.S.,Shenbagapriya,P.,Nair,S.C.,George,B.,Mathews,V.,Chandy,M.,Viswabandya,A.,Srivastava,A.,2013.Molecular basis of quantitative fibrinogen disorders in 27 patients from India.Haemophilia 19,611e618.
Thomas,S.,Legendre,M.,Saunier,S.,Bessieres,B.,Alby,C.,Bonniere,M.,Toutain,A.,Loeuillet,L.,Szymanska,K.,Jossic,F.,Gaillard,D.,Yacoubi,M.T.,MougouZerelli,S.,David,A.,Barthez,M.A.,Ville,Y.,Bole-Feysot,C.,Nitschke,P.,Lyonnet,S.,Munnich,A.,Johnson,C.A.,Encha-Razavi,F.,Cormier-Daire,V.,Thauvin-Robinet,C.,Vekemans,M.,Attie-Bitach,T.,2012.TCTN3 mutations cause Mohr-Majewski syndrome.Am.J.Hum.Genet.91,372e378.
Traboulsi,E.I.,2004.Congenital abnormalities of cranial nerve development:overview,molecular mechanisms,and further evidence of heterogeneity and complexity of syndromes with congenital limitation of eye movements.Trans.Am.Ophthalmol.Soc.102,373e389.
Traeger-Synodinos,J.,2017.Pre-implantation genetic diagnosis.Best Pract.Res.Clin.Obstet.Gynaecol.39,74e88.
Tsurusaki,Y.,Yonezawa,R.,Furuya,M.,Nishimura,G.,Pooh,R.K.,Nakashima,M.,Saitsu,H.,Miyake,N.,Saito,S.,Matsumoto,N.,2014.Whole exome sequencing revealed biallelic IFT122 mutations in a family with CED1 and recurrent pregnancy loss.Clin.Genet.85,592e594.
Tur-Torres,M.H.,Garrido-Gimenez,C.,Alijotas-Reig,J.,2017.Genetics of recurrent miscarriage and fetal loss.Best Pract.Res.Clin.Obstet.Gynaecol.42,11e25.
Valente,E.M.,Logan,C.V.,Mougou-Zerelli,S.,Lee,J.H.,Silhavy,J.L.,Brancati,F.,Iannicelli,M.,Travaglini,L.,Romani,S.,Illi,B.,Adams,M.,Szymanska,K.,Mazzotta,A.,Lee,J.E.,Tolentino,J.C.,Swistun,D.,Salpietro,C.D.,Fede,C.,Gabriel,S.,Russ,C.,Cibulskis,K.,Sougnez,C.,Hildebrandt,F.,Otto,E.A.,Held,S.,Diplas,B.H.,Davis,E.E.,Mikula,M.,Strom,C.M.,Ben-Zeev,B.,Lev,D.,Sagie,T.L.,Michelson,M.,Yaron,Y.,Krause,A.,Boltshauser,E.,Elkhartoufi,N.,Roume,J.,Shalev,S.,Munnich,A.,Saunier,S.,Inglehearn,C.,Saad,A.,Alkindy,A.,Thomas,S.,Vekemans,M.,Dallapiccola,B.,Katsanis,N.,Johnson,C.A.,AttieBitach,T.,Gleeson,J.G.,2010.Mutations in TMEM216 perturb ciliogenesis and cause Joubert,Meckel and related syndromes.Nat.Genet.42,619e625.
van den Berg,M.M.,van Maarle,M.C.,van Wely,M.,Goddijn,M.,2012.Genetics of early miscarriage.Biochim.Biophys.Acta 1822,1951-199.
van den Boogaard,E.,Kaandorp,S.P.,Franssen,M.T.,Mol,B.W.,Leschot,N.J.,Wouters,C.H.,van der Veen,F.,Korevaar,J.C.,Goddijn,M.,2010.Consecutive or non-consecutive recurrent miscarriage:is there any difference in carrier status?Hum.Reprod.25,1411e1414.
van den Veyver,I.B.,Eng,C.M.,2015.Genome-wide sequencing for prenatal detection of fetal single-gene disorders.Cold Spring Harb.Perspect.Med.5,a023077.
Vimercati,A.,Grasso,S.,Abruzzese,M.,Chincoli,A.,de Gennaro,A.,Miccolis,A.,Serio,G.,Selvaggi,L.,Fascilla,F.D.,2012.Correlation between ultrasound diagnosis and autopsy findings of fetal malformations.J.Prenat.Med.6,13e17.
Vora,N.,Powell,B.,Brandt,A.,Strande,N.,Hardisty,E.,Gilmore,K.,Katherine MForeman,A.,Wilhelmsen,K.,Bizon,C.,Reilly,J.,Owen,P.,M Powell,C.,Skinner,D.,Rini,C.,D Lyerly,A.,A Boggess,K.,Weck,K.,Berg,J.,P Evans,J.,2017.Prenatal exome sequencing in anomalous fetuses:new opportunities and challenges.Genet.Med.19,1207e1216.
Walczak-Sztulpa,J.,Eggenschwiler,J.,Osborn,D.,Brown,D.A.,Emma,F.,Klingenberg,C.,Hennekam,R.C.,Torre,G.,Garshasbi,M.,Tzschach,A.,Szczepanska,M.,Krawczynski,M.,Zachwieja,J.,Zwolinska,D.,Beales,P.L.,Ropers,H.H.,Latos-Bielenska,A.,Kuss,A.W.,2010.Cranioectodermal dysplasia,sensenbrenner syndrome,is a ciliopathy caused by mutations in the IFT122gene.Am.J.Hum.Genet.86,949e956.
Wang,Z.,Yang,Z.,Ke,Z.,Yang,S.,Shi,H.,Wang,L.,2009.Mutations in COL1A1 of type I collagen genes in Chinese patients with osteogenesis imperfecta.J.Investig.Med.57,662e667.
Wieacker,P.,Steinhard,J.,2010.The prenatal diagnosis of genetic diseases.Dtsch.Arztebl.Int.107,857e862.
Witters,G.,Van Robays,J.,Willekes,C.,Coumans,A.,Peeters,H.,Gyselaers,W.,Fryns,J.P.,2011.Trisomy 13,18,21,Triploidy and turner syndrome:the 5T's.Look at the hands.Facts Views Vis.Obgyn.3,15e21.
Wright,C.F.,FitzPatrick,D.R.,Firth,H.V.,2018 May.Paediatric genomics:diagnosing rare disease in children.Nat.Rev.Genet.19,325.
Xu,Y.,Shi,Y.,Fu,J.,Yu,M.,Feng,R.,Sang,Q.,Liang,B.,Chen,B.,Qu,R.,Li,B.,Yan,Z.,Mao,X.,Kuang,Y.,Jin,L.,He,L.,Sun,X.,Wang,L.,2016.Mutations in PADI6 cause female infertility characterized by early embryonic arrest.Am.J.Hum.Genet.99,744e752.
Yan,L.,Huang,L.,Xu,L.,Huang,J.,Ma,F.,Zhu,X.,Tang,Y.,Liu,M.,Lian,Y.,Liu,P.,Li,R.,Lu,S.,Tang,F.,Qiao,J.,Xie,X.S.,2015.Live births after simultaneous avoidance of monogenic diseases and chromosome abnormality by nextgeneration sequencing with linkage analyses.Proc.Natl.Acad.Sci.U.S.A.112,15964e15969.
Yang,Y.,Muzny,D.M.,Reid,J.G.,Bainbridge,M.N.,Willis,A.,Ward,P.A.,Braxton,A.,Beuten,J.,Xia,F.,Niu,Z.,Hardison,M.,Person,R.,Bekheirnia,M.R.,Leduc,M.S.,Kirby,A.,Pham,P.,Scull,J.,Wang,M.,Ding,Y.,Plon,S.E.,Lupski,J.R.,Beaudet,A.L.,Gibbs,R.A.,Eng,C.M.,2013.Clinical whole-exome sequencing for the diagnosis of mendelian disorders.N.Engl.J.Med.369,1502e1511.
Yang,Y.,Muzny,D.M.,Xia,F.,Niu,Z.,Person,R.,Ding,Y.,Ward,P.,Braxton,A.,Wang,M.,Buhay,C.,Veeraraghavan,N.,Hawes,A.,Chiang,T.,Leduc,M.,Beuten,J.,Zhang,J.,He,W.,Scull,J.,Willis,A.,Landsverk,M.,Craigen,W.J.,Bekheirnia,M.R.,Stray-Pedersen,A.,Liu,P.,Wen,S.,Alcaraz,W.,Cui,H.,Walkiewicz,M.,Reid,J.,Bainbridge,M.,Patel,A.,Boerwinkle,E.,Beaudet,A.L.,Lupski,J.R.,Plon,S.E.,Gibbs,R.A.,Eng,C.M.,2014.Molecular findings among patients referred for clinical whole-exome sequencing.J.Am.Med.Assoc.312,1870e1879.
Yates,C.L.,Monaghan,K.G.,Copenheaver,D.,Retterer,K.,Scuffins,J.,Kucera,C.R.,Friedman,B.,Richard,G.,Juusola,J.,2017.Whole-exome sequencing on deceased fetuses with ultrasound anomalies:expanding our knowledge of genetic disease during fetal development.Genet.Med.19,1171e1178.
Alazami,A.M.,Awad,S.M.,Coskun,S.,Al-Hassan,S.,Hijazi,H.,Abdulwahab,F.M.,Poizat,C.,Alkuraya,F.S.,2015.TLE6 mutation causes the earliest known human embryonic lethality.Genome Biol.16,240.
ASRM,2013.Definitions of infertility and recurrent pregnancy loss:a committee opinion.Fertil.Steril.99,63.
Asadollahi,R.,Oneda,B.,Joset,P.,Azzarello-Burri,S.,Bartholdi,D.,Steindl,K.,Vincent,M.,Cobilanschi,J.,Sticht,H.,Baldinger,R.,Reissmann,R.,Sudholt,I.,Thiel,C.T.,Ekici,A.B.,Reis,A.,Bijlsma,E.K.,Andrieux,J.,Dieux,A.,FitzPatrick,D.,Ritter,S.,Baumer,A.,Latal,B.,Plecko,B.,Jenni,O.G.,Rauch,A.,2014.The clinical significance of small copy number variants in neurodevelopmental disorders.J.Med.Genet.51,677e688.
Asselta,R.,Spena,S.,Duga,S.,Tenchini,M.L.,2007.Molecular genetics of quantitative fibrinogen disorders.Cardiovasc.Hematol.Agents Med.Chem.5,163e173.
Bamshad,M.J.,Shendure,J.A.,Valle,D.,Hamosh,A.,Lupski,J.R.,Gibbs,R.A.,Boerwinkle,E.,Lifton,R.P.,Gerstein,M.,Gunel,M.,Mane,S.,Nickerson,D.A.,2012.The Centers for Mendelian Genomics:a new large-scale initiative to identify the genes underlying rare Mendelian conditions.Am.J.Med.Genet.158A,1523e1525.
Bao,R.,Huang,L.,Andrade,J.,Tan,W.,Kibbe,W.A.,Jiang,H.,Feng,G.,2014.Review of current methods,applications,and data management for the bioinformatics analysis of whole exome sequencing.Cancer Inform.13,67e82.
Bhuiyan,Z.A.,Momenah,T.S.,Gong,Q.,Amin,A.S.,Ghamdi,S.A.,Carvalho,J.S.,Homfray,T.,Mannens,M.M.,Zhou,Z.,Wilde,A.A.,2008.Recurrent intrauterine fetal loss due to near absence of HERG:clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation.Heart Rhythm.5,553e561.
Boycott,K.M.,Rath,A.,Chong,J.X.,Hartley,T.,Alkuraya,F.S.,Baynam,G.,Brookes,A.J.,Brudno,M.,Carracedo,A.,den Dunnen,J.T.,Dyke,S.,Estivill,X.,Goldblatt,J.,Gonthier,C.,Groft,S.C.,Gut,I.,Hamosh,A.,Hieter,P.,Hohn,S.,Hurles,M.E.,Kaufmann,P.,Knoppers,B.M.,Krischer,J.P.,Macek,M.J.,Matthijs,G.,Olry,A.,Parker,S.,Paschall,J.,Philippakis,A.A.,Rehm,H.L.,Robinson,P.N.,Sham,P.C.,Stefanov,R.,Taruscio,D.,Unni,D.,Vanstone,M.R.,Zhang,F.,Brunner,H.,Bamshad,M.J.,Lochmuller,H.,2017.International cooperation to enable the diagnosis of all rare genetic diseases.Am.J.Hum.Genet.100,695e705.
Boycott,K.M.,Vanstone,M.R.,Bulman,D.E.,MacKenzie,A.E.,2013.Rare-disease genetics in the era of next-generation sequencing:discovery to translation.Nat.Rev.Genet.14,681e691.
Boyd,P.A.,Tondi,F.,Hicks,N.R.,Chamberlain,P.F.,2004.Autopsy after termination of pregnancy for fetal anomaly:retrospective cohort study.BMJ 328,137.
Brown,T.L.,Meloche,T.M.,2016.Exome sequencing a review of new strategies for rare genomic disease research.Genomics 108,109e114.
Carss,K.J.,Hillman,S.C.,Parthiban,V.,McMullan,D.J.,Maher,E.R.,Kilby,M.D.,Hurles,M.E.,2014.Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound.Hum.Mol.Genet.23,3269e3277.
CDC,2008.Update on overall prevalence of major birth defects-Atlanta,Georgia,1978-2005.MMWR Morb.Mortal.Wkly.Rep.57,1e5.
Choi,M.,Scholl,U.I.,Ji,W.,Liu,T.,Tikhonova,I.R.,Zumbo,P.,Nayir,A.,Bakkaloglu,A.,Ozen,S.,Sanjad,S.,Nelson-Williams,C.,Farhi,A.,Mane,S.,Lifton,R.P.,2009.Genetic diagnosis by whole exome capture and massively parallel DNAsequencing.Proc.Natl.Acad.Sci.U.S.A.106,19096e19101.
Chong,J.X.,Buckingham,K.J.,Jhangiani,S.N.,Boehm,C.,Sobreira,N.,Smith,J.D.,Harrell,T.M.,McMillin,M.J.,Wiszniewski,W.,Gambin,T.,Coban,A.Z.,Doheny,K.,Scott,A.F.,Avramopoulos,D.,Chakravarti,A.,Hoover-Fong,J.,Mathews,D.,Witmer,P.D.,Ling,H.,Hetrick,K.,Watkins,L.,Patterson,K.E.,Reinier,F.,Blue,E.,Muzny,D.,Kircher,M.,Bilguvar,K.,Lopez-Giraldez,F.,Sutton,V.R.,Tabor,H.K.,Leal,S.M.,Gunel,M.,Mane,S.,Gibbs,R.A.,Boerwinkle,E.,Hamosh,A.,Shendure,J.,Lupski,J.R.,Lifton,R.P.,Valle,D.,Nickerson,D.A.,Bamshad,M.J.,2015.The genetic basis of Mendelian phenotypes:discoveries,challenges,and opportunities.Am.J.Hum.Genet.97,199e215.
Cobourne,M.T.,2004.The complex genetics of cleft lip and palate.Eur.J.Orthod.26,7e16.
Dai,L.,Zhu,J.,Mao,M.,Li,Y.,Deng,Y.,Wang,Y.,Liang,J.,Tang,L.,Wang,H.,Kilfoy,B.A.,Zheng,T.,Zhang,Y.,2010.Time trends in oral clefts in Chinese newborns:data from the Chinese National Birth Defects Monitoring Network.Birth Defects Res.A Clin.Mol.Teratol.88,41e47.
D'Amours,G.,Kibar,Z.,Mathonnet,G.,Fetni,R.,Tihy,F.,Desilets,V.,Nizard,S.,Michaud,J.L.,Lemyre,E.,2012.Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype.Clin.Genet.81,128e141.
Dickinson,M.E.,Flenniken,A.M.,Ji,X.,Teboul,L.,Wong,M.D.,White,J.K.,Meehan,T.F.,Weninger,W.J.,Westerberg,H.,Adissu,H.,Baker,C.N.,Bower,L.,Brown,J.M.,Caddle,L.B.,Chiani,F.,Clary,D.,Cleak,J.,Daly,M.J.,Denegre,J.M.,Doe,B.,Dolan,M.E.,Edie,S.M.,Fuchs,H.,Gailus-Durner,V.,Galli,A.,Gambadoro,A.,Gallegos,J.,Guo,S.,Horner,N.R.,Hsu,C.W.,Johnson,S.J.,Kalaga,S.,Keith,L.C.,Lanoue,L.,Lawson,T.N.,Lek,M.,Mark,M.,Marschall,S.,Mason,J.,McElwee,M.L.,Newbigging,S.,Nutter,L.M.,Peterson,K.A.,RamirezSolis,R.,Rowland,D.J.,Ryder,E.,Samocha,K.E.,Seavitt,J.R.,Selloum,M.,SzokeKovacs,Z.,Tamura,M.,Trainor,A.G.,Tudose,I.,Wakana,S.,Warren,J.,Wendling,O.,West,D.B.,Wong,L.,Yoshiki,A.,MacArthur,D.G.,TocchiniValentini,G.P.,Gao,X.,Flicek,P.,Bradley,A.,Skarnes,W.C.,Justice,M.J.,Parkinson,H.E.,Moore,M.,Wells,S.,Braun,R.E.,Svenson,K.L.,de Angelis,M.H.,Herault,Y.,Mohun,T.,Mallon,A.M.,Henkelman,R.M.,Brown,S.D.,Adams,D.J.,Lloyd,K.C.,McKerlie,C.,Beaudet,A.L.,Bucan,M.,Murray,S.A.,2016.Highthroughput discovery of novel developmental phenotypes.Nature 537,508e514.
Dinwiddie,D.L.,Smith,L.D.,Miller,N.A.,Atherton,A.M.,Farrow,E.G.,Strenk,M.E.,Soden,S.E.,Saunders,C.J.,Kingsmore,S.F.,2013.Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome.Genomics 102,148e156.
Dixon,M.J.,Marazita,M.L.,Beaty,T.H.,Murray,J.C.,2011.Cleft lip and palate:understanding genetic and environmental influences.Nat.Rev.Genet.12,167e178.
Drury,S.,Boustred,C.,Tekman,M.,Stanescu,H.,Kleta,R.,Lench,N.,Chitty,L.S.,Scott,R.H.,2014.A novel homozygous ERCC5 truncating mutation in a family with prenatal arthrogryposis-further evidence of genotype-phenotype correlation.Am.J.Med.Genet.164A,1777e1783.
Drury,S.,Williams,H.,Trump,N.,Boustred,C.,Lench,N.,Scott,R.H.,Chitty,L.S.,2015.Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities.Prenat.Diagn.35,1010e1017.
Ellard,S.,Kivuva,E.,Turnpenny,P.,Stals,K.,Johnson,M.,Xie,W.,Caswell,R.,Lango,A.H.,2015.An exome sequencing strategy to diagnose lethal autosomal recessive disorders.Eur.J.Hum.Genet.23,401e404.
Falardeau,F.,Camurri,M.V.,Campeau,P.M.,2017.Genomic approaches to diagnose rare bone disorders.Bone 102,5e14.
Filges,I.,Friedman,J.M.,2015.Exome sequencing for gene discovery in lethal fetal disorders-harnessing the value of extreme phenotypes.Prenat.Diagn.35,1005e1009.
Filges,I.,Manokhina,I.,Penaherrera,M.S.,McFadden,D.E.,Louie,K.,Nosova,E.,Friedman,J.M.,Robinson,W.P.,2015.Recurrent triploidy due to a failure to complete maternal meiosis II:whole-exome sequencing reveals candidate variants.Mol.Hum.Reprod.21,339e346.
Filges,I.,Nosova,E.,Bruder,E.,Tercanli,S.,Townsend,K.,Gibson,W.T.,Rothlisberger,B.,Heinimann,K.,Hall,J.G.,Gregory-Evans,C.Y.,Wasserman,W.W.,Miny,P.,Friedman,J.M.,2014.Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype.Clin.Genet.86,220e228.
FitzPatrick,D.R.,et al.,2003.Identification of SATB2 as the cleft palate gene on2q32-q33.Hum.Mol.Genet.12,2491e2501.
Forlino,A.,Marini,J.C.,2016.Osteogenesis imperfecta.Lancet 387,1657e1671.
Geister,K.A.,Camper,S.A.,2015.Advances in skeletal dysplasia genetics.Annu.Rev.Genomics Hum.Genet.16,199e227.
Gelb,B.,Brueckner,M.,Chung,W.,Goldmuntz,E.,Kaltman,J.,Kaski,J.P.,Kim,R.,Kline,J.,Mercer-Rosa,L.,Porter,G.,Roberts,A.,Rosenberg,E.,Seiden,H.,Seidman,C.,Sleeper,L.,Tennstedt,S.,Kaltman,J.,Schramm,C.,Burns,K.,Pearson,G.,Rosenberg,E.,2013.The congenital heart disease genetic network study:rationale,design,and early results.Circ.Res.112,698e706.
Giannandrea,M.,Parks,W.C.,2014.Diverse functions of matrix metalloproteinases during fibrosis.Dis.Model Mech.7,193e203.
Guo,C.,Wang,Q.,Wang,Y.,Yang,L.,Luo,H.,Cao,X.F.,An,L.,Qiu,Y.,Du,M.,Ma,X.,Li,H.,Lu,C.,2017.Exome sequencing reveals novel IRXI mutation in congenital heart disease.Mol.Med.Rep.15,3193e3197.
Handyside,A.H.,Kontogianni,E.H.,Hardy,K.,Winston,R.M.,1990.Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification.Nature 344,768e770.
Hiersch,L.,Reches,A.,Simchoni,S.,Barel,D.,Greenberg,R.,Ben Sira,L.,Gustavo,M.,Y,Y.,2017.The added yield of whole exome sequencing in fetuses with suspected central nervous system abnormalities.In:Proceedings of 16th World Congress in Fetal Medicine,Ljubljana,Slovenia.
Hyde,K.J.,Schust,D.J.,2015.Genetic considerations in recurrent pregnancy loss.Cold Spring Harb.Perspect.Med.5,a023119.
Itoh,T.,Shirahama,S.,Nakashima,E.,Maeda,K.,Haga,N.,Kitoh,H.,Kosaki,R.,Ohashi,H.,Nishimura,G.,Ikegawa,S.,2006.Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population.Am.J.Med.Genet.140,1280e1284.
Jia,Z.,Fengbiao,M.,Wang,L.,Li,M.,Shi,Y.,Zhang,B.,Gao,G.,2017.Whole-exome sequencing identifies a de novo mutation in TRPM4 involved in pleiotropic ventricular septal defect.Int.J.Clin.Exp.Pathol.10,5092e5104.
Laurino,M.Y.,Bennett,R.L.,Saraiya,D.S.,Baumeister,L.,Doyle,D.L.,Leppig,K.,Pettersen,B.,Resta,R.,Shields,L.,Uhrich,S.,Varga,E.A.,Raskind,W.H.,2005.Genetic evaluation and counseling of couples with recurrent miscarriage:recommendations of the National Society of Genetic Counselors.J.Genet.Couns.14,165e181.
Lee,H.,Deignan,J.L.,Dorrani,N.,Strom,S.P.,Kantarci,S.,Quintero-Rivera,F.,Das,K.,Toy,T.,Harry,B.,Yourshaw,M.,Fox,M.,Fogel,B.L.,Martinez-Agosto,J.A.,Wong,D.A.,Chang,V.Y.,Shieh,P.B.,Palmer,C.G.,Dipple,K.M.,Grody,W.W.,Vilain,E.,Nelson,S.F.,2014.Clinical exome sequencing for genetic identification of rare Mendelian disorders.J.Am.Med.Assoc.312,1880e1887.
Lee,V.,Chow,J.,Yeung,W.,Ho,P.C.,2017.Preimplantation genetic diagnosis for monogenic diseases.Best Pract.Res.Clin.Obstet.Gynaecol.44,68e75.
Lewis,A.J.,Austin,E.,Knapp,R.,Vaiano,T.,Galbally,M.,2015.Perinatal maternal mental health,fetal programming and child development.Healthcare(Basel)3,1212e1227.
Li,T.C.,Makris,M.,Tomsu,M.,Tuckerman,E.,Laird,S.,2002.Recurrent miscarriage:aetiology,management and prognosis.Hum.Reprod.Update 8,463e481.
Lohmann,K.,Klein,C.,2014.Next generation sequencing and the future of genetic diagnosis.Neurotherapeutics 11,699e707.
Mademont-Soler,I.,Morales,C.,Soler,A.,Martinez-Crespo,J.M.,Shen,Y.,Margarit,E.,Clusellas,N.,Obon,M.,Wu,B.L.,Sanchez,A.,2013.Prenatal diagnosis of chromosomal abnormalities in fetuses with abnormal cardiac ultrasound findings:evaluation of chromosomal microarray-based analysis.Ultrasound Obstet.Gynecol.41,375e382.
Marazita,M.L.,Mooney,M.P.,2004 Apr.Current concepts in the embryology and genetics of cleft lip and cleft palate.Clin.Plast.Surg.31(2),125e140.
Marokakis,S.,Kasparian,N.A.,Kennedy,S.E.,2016.Prenatal counselling for congenital anomalies:a systematic review.Prenat.Diagn.36,662e671.
McCulley,D.J.1,Black,B.L.,2012.Transcription factor pathways and congenital heart disease.Curr.Top Dev.Biol.100,253e277.
McInerney-Leo,A.M.,Schmidts,M.,Cortes,C.R.,Leo,P.J.,Gener,B.,Courtney,A.D.,Gardiner,B.,Harris,J.A.,Lu,Y.,Marshall,M.,Scambler,P.J.,Beales,P.L.,Brown,M.A.,Zankl,A.,Mitchison,H.M.,Duncan,E.L.,Wicking,C.,2013.Shortrib polydactyly and Jeune syndromes are caused by mutations in WDR60.Am.J.Hum.Genet.93,515e523.
Mills,J.L.,2010.Malformations in infants of diabetic mothers.Teratology 25,385e394,1982.Birth Defects Res.A Clin.Mol.Teratol.88,769-778.
Mitchell,K.,O'Sullivan,J.,Missero,C.,Blair,E.,Richardson,R.,Anderson,B.,Antonini,D.,Murray,J.C.,Shanske,A.L.,Schutte,B.C.,Romano,R.A.,Sinha,S.,Bhaskar,S.S.,Black,G.C.,Dixon,J.,Dixon,M.J.,2012.Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus.Am.J.Hum.Genet.90,69e75.
Mossey,P.A.,Little,J.,Munger,R.G.,Dixon,M.J.,Shaw,W.C.,2009.Cleft lip and palate.Lancet 374,1773e1785.
Moyers,S.,Bailey,L.B.,2001.Fetal malformations and folate metabolism:review of recent evidence.Nutr.Rev.59,215e224.
Ng,S.B.,Buckingham,K.J.,Lee,C.,Bigham,A.W.,Tabor,H.K.,Dent,K.M.,Huff,C.D.,Shannon,P.T.,Jabs,E.W.,Nickerson,D.A.,Shendure,J.,Bamshad,M.J.,2010.Exome sequencing identifies the cause of a mendelian disorder.Nat.Genet.42,30e35.
Ng,S.B.,Turner,E.H.,Robertson,P.D.,Flygare,S.D.,Bigham,A.W.,Lee,C.,Shaffer,T.,Wong,M.,Bhattacharjee,A.,Eichler,E.E.,Bamshad,M.,Nickerson,D.A.,Shendure,J.,2009.Targeted capture and massively parallel sequencing of 12human exomes.Nature 461,272e276.
Ornoy,A.,Ergaz,Z.,2010.Alcohol abuse in pregnant women:effects on the fetus and newborn,mode of action and maternal treatment.Int.J.Environ.Res.Public Health 7,364e379.
Osoegawa,K.,Vessere,G.M.,Utami,K.H.,Mansilla,M.A.,Johnson,M.K.,Riley,B.M.,L'Heureux,J.,Pfundt,R.,Staaf,J.,van der Vliet,W.A.,Lidral,A.C.,Schoenmakers,E.F.,Borg,A.,Schutte,B.C.,Lammer,E.J.,Murray,J.C.,de Jong,P.J.,2008.Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridisation.J.Med.Genet.45,81e86.
Ottaviani,G.,Buja,L.M.,2017 Jul.Update on congenital heart disease and sudden infant/perinatal death:from history to future trends.J.Clin.Pathol.70(7),555e562.
Page,J.M.,Silver,R.M.,2016.Genetic causes of recurrent pregnancy loss.Clin.Obstet.Gynecol.59,498e508.
Pangalos,C.,Hagnefelt,B.,Lilakos,K.,Konialis,C.,2016.First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects.PeerJ 4e1955.
Pinto,A.M.,Imperatore,V.,Bianciardi,L.,Baldassarri,M.,Galluzzi,P.,Furini,S.,Centini,G.,Renieri,A.,Mari,F.,2017.Combined ultrasound and exome sequencing approach recognizes Opitz G/BBB syndrome in two malformed fetuses.Clin.Dysmorphol.26,18e25.
Putoux,A.,Thomas,S.,Coene,K.L.,Davis,E.E.,Alanay,Y.,Ogur,G.,Uz,E.,Buzas,D.,Gomes,C.,Patrier,S.,Bennett,C.L.,Elkhartoufi,N.,Frison,M.H.,Rigonnot,L.,Joye,N.,Pruvost,S.,Utine,G.E.,Boduroglu,K.,Nitschke,P.,Fertitta,L.,ThauvinRobinet,C.,Munnich,A.,Cormier-Daire,V.,Hennekam,R.,Colin,E.,Akarsu,N.A.,Bole-Feysot,C.,Cagnard,N.,Schmitt,A.,Goudin,N.,Lyonnet,S.,Encha-Razavi,F.,Siffroi,J.P.,Winey,M.,Katsanis,N.,Gonzales,M.,Vekemans,M.,Beales,P.L.,Attie-Bitach,T.,2011.KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes.Nat.Genet.43,601e606.
Qiao,Y.,Wen,J.,Tang,F.,Martell,S.,Shomer,N.,Leung,P.C.,Stephenson,M.D.,Rajcan-Separovic,E.,2016.Whole exome sequencing in recurrent early pregnancy loss.Mol.Hum.Reprod.22,364e372.
Quintero-Ronderos,P.,Mercier,E.,Fukuda,M.,Gonzalez,R.,Suarez,C.F.,Patarroyo,M.A.,Vaiman,D.,Gris,J.C.,Laissue,P.,2017.Novel genes and mutations in patients affected by recurrent pregnancy loss.PLoS One 12,e0186149.
Rabbani,B.,Tekin,M.,Mahdieh,N.,2014.The promise of whole-exome sequencing in medical genetics.J.Hum.Genet.59,5e15.
Ramos,E.I.,Bien-Willner,G.A.,Li,J.,Hughes,A.E.,Giacalone,J.,Chasnoff,S.,Kulkarni,S.,Parmacek,M.,Cole,F.S.,Druley,T.E.,2014.Genetic variation in MKL2 and decreased downstream PCTAIRE1 expression in extreme,fatal primary human microcephaly.Clin.Genet.85,423e432.
Retterer,K.,Juusola,J.,Cho,M.T.,Vitazka,P.,Millan,F.,Gibellini,F.,Vertino-Bell,A.,Smaoui,N.,Neidich,J.,Monaghan,K.G.,McKnight,D.,Bai,R.,Suchy,S.,Friedman,B.,Tahiliani,J.,Pineda-Alvarez,D.,Richard,G.,Brandt,T.,Haverfield,E.,Chung,W.K.,Bale,S.,2016.Clinical application of whole-exome sequencing across clinical indications.Genet.Med.18,696e704.
Romani,M.,Micalizzi,A.,Valente,E.M.,2013.Joubert syndrome:congenital cerebellar ataxia with the molar tooth.Lancet Neurol.12,894e905.
Roosing,S.,Romani,M.,Isrie,M.,Rosti,R.O.,Micalizzi,A.,Musaev,D.,Mazza,T.,AlGazali,L.,Altunoglu,U.,Boltshauser,E.,D'Arrigo,S.,De Keersmaecker,B.,Kayserili,H.,Brandenberger,S.,Kraoua,I.,Mark,P.R.,McKanna,T.,Van Keirsbilck,J.,Moerman,P.,Poretti,A.,Puri,R.,Van Esch,H.,Gleeson,J.G.,Valente,E.M.,2016.Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.J.Med.Genet.53,608e615.
Rossi,A.C.,Prefumo,F.,2013.Accuracy of ultrasonography at 11-14 weeks of gestation for detection of fetal structural anomalies:a systematic review.Obstet.Gynecol.122,1160e1167.
Sanders,A.A.,de Vrieze,E.,Alazami,A.M.,Alzahrani,F.,Malarkey,E.B.,Sorusch,N.,Tebbe,L.,Kuhns,S.,van Dam,T.J.,Alhashem,A.,Tabarki,B.,Lu,Q.,Lambacher,N.J.,Kennedy,J.E.,Bowie,R.V.,Hetterschijt,L.,van Beersum,S.,van Reeuwijk,J.,Boldt,K.,Kremer,H.,Kesterson,R.A.,Monies,D.,Abouelhoda,M.,Roepman,R.,Huynen,M.H.,Ueffing,M.,Russell,R.B.,Wolfrum,U.,Yoder,B.K.,van Wijk,E.,Alkuraya,F.S.,Blacque,O.E.,2015.KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome.Genome Biol.16,293.
Sawyer,S.L.,Hartley,T.,Dyment,D.A.,Beaulieu,C.L.,Schwartzentruber,J.,Smith,A.,Bedford,H.M.,Bernard,G.,Bernier,F.P.,Brais,B.,Bulman,D.E.,Warman,C.J.,Chitayat,D.,Deladoey,J.,Fernandez,B.A.,Frosk,P.,Geraghty,M.T.,Gerull,B.,Gibson,W.,Gow,R.M.,Graham,G.E.,Green,J.S.,Heon,E.,Horvath,G.,Innes,A.M.,Jabado,N.,Kim,R.H.,Koenekoop,R.K.,Khan,A.,Lehmann,O.J.,Mendoza-Londono,R.,Michaud,J.L.,Nikkel,S.M.,Penney,L.S.,Polychronakos,C.,Richer,J.,Rouleau,G.A.,Samuels,M.E.,Siu,V.M.,Suchowersky,O.,Tarnopolsky,M.A.,Yoon,G.,Zahir,F.R.,Majewski,J.,Boycott,K.M.,2016.Utility of whole-exome sequencing for those near the end of the diagnostic odyssey:time to address gaps in care.Clin.Genet.89,275 e284.
Scapoli,L.,Martinelli,M.,Arlotti,M.,Palmieri,A.,Masiero,E.,Pezzetti,F.,Carinci,F.,2008.Genes causing clefting syndromes as candidates for non-syndromic cleft lip with or without cleft palate:a family-based association study.Eur.J.Oral Sci.116,507e511.
Shamseldin,H.E.,Swaid,A.,Alkuraya,F.S.,2013.Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing.Genet.Med.15,307e309.
Shamseldin,H.E.,Kurdi,W.,Almusafri,F.,Alnemer,M.,Alkaff,A.,Babay,Z.,Alhashem,A.,Tulbah,M.,Alsahan,N.,Khan,R.,Sallout,B.,Al Mardawi,E.,Seidahmed,M.Z.,Meriki,N.,Alsaber,Y.,Qari,A.,Khalifa,O.,Eyaid,W.,Rahbeeni,Z.,Kurdi,A.,Hashem,M.,Alshidi,T.,Al-Obeid,E.,Abdulwahab,F.,Ibrahim,N.,Ewida,N.,El-Akouri,K.,Al Mulla,M.,Ben-Omran,T.,Pergande,M.,Cirak,S.,Al Tala,S.,Shaheen,R.,Faqeih,E.,Alkuraya,F.S.,2018 Apr.Molecular autopsy in maternal-fetal medicine.Genet.Med.20(4),420e427.
Shamseldin,H.E.,Tulbah,M.,Kurdi,W.,Nemer,M.,Alsahan,N.,Al,M.E.,Khalifa,O.,Hashem,A.,Kurdi,A.,Babay,Z.,Bubshait,D.K.,Ibrahim,N.,Abdulwahab,F.,Rahbeeni,Z.,Hashem,M.,Alkuraya,F.S.,2015.Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families.Genome Biol.16,116.
Sierra,S.,Stephenson,M.,2006.Genetics of recurrent pregnancy loss.Semin.Reprod.Med.24,17e24.
Silasi,M.,Cardenas,I.,Kwon,J.Y.,Racicot,K.,Aldo,P.,Mor,G.,2015.Viral infections during pregnancy.Am.J.Reprod.Immunol.73,199e213.
Soden,S.E.,Saunders,C.J.,Willig,L.K.,Farrow,E.G.,Smith,L.D.,Petrikin,J.E.,Le Pichon,J.B.,Miller,N.A.,Thiffault,I.,Dinwiddie,D.L.,Twist,G.,Noll,A.,Heese,B.A.,Zellmer,L.,Atherton,A.M.,Abdelmoity,A.T.,Safina,N.,Nyp,S.S.,Zuccarelli,B.,Larson,I.A.,Modrcin,A.,Herd,S.,Creed,M.,Ye,Z.,Yuan,X.,Brodsky,R.A.,Kingsmore,S.F.,2014.Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.Sci.Transl.Med.6,265ra168.
Stals,K.L.,Wakeling,M.,Baptista,J.,Caswell,R.,Parrish,A.,Rankin,J.,Tysoe,C.,Jones,G.,Gunning,A.C.,Lango,A.H.,Bradley,L.,Brady,A.F.,Carley,H.,Carmichael,J.,Castle,B.,Cilliers,D.,Cox,H.,Deshpande,C.,Dixit,A.,Eason,J.,Elmslie,F.,Fry,A.E.,Fryer,A.,Holder,M.,Homfray,T.,Kivuva,E.,McKay,V.,Newbury-Ecob,R.,Parker,M.,Savarirayan,R.,Searle,C.,Shannon,N.,Shears,D.,Smithson,S.,Thomas,E.,Turnpenny,P.D.,Varghese,V.,Vasudevan,P.,Wakeling,E.,Baple,E.L.,Ellard,S.,2018.Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.Prenat.Diagn.38,33e43.
Stark,Z.,Tan,T.Y.,Chong,B.,Brett,G.R.,Yap,P.,Walsh,M.,Yeung,A.,Peters,H.,Mordaunt,D.,Cowie,S.,Amor,D.J.,Savarirayan,R.,McGillivray,G.,Downie,L.,Ekert,P.G.,Theda,C.,James,P.A.,Yaplito-Lee,J.,Ryan,M.M.,Leventer,R.J.,Creed,E.,Macciocca,I.,Bell,K.M.,Oshlack,A.,Sadedin,S.,Georgeson,P.,Anderson,C.,Thorne,N.,Melbourne,G.H.A.,Gaff,C.,White,S.M.,2016.A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.Genet.Med.18,1090e1096.
Stern,H.J.,2014.Preimplantation genetic diagnosis:prenatal testing for embryos finally achieving its potential.J.Clin.Med.3,280e309.
Stranneheim,H.,Wedell,A.,2016.Exome and genome sequencing:a revolution for the discovery and diagnosis of monogenic disorders.J.Intern.Med.279,3e15.
Sumitha,E.,Jayandharan,G.R.,Arora,N.,Abraham,A.,David,S.,Devi,G.S.,Shenbagapriya,P.,Nair,S.C.,George,B.,Mathews,V.,Chandy,M.,Viswabandya,A.,Srivastava,A.,2013.Molecular basis of quantitative fibrinogen disorders in 27 patients from India.Haemophilia 19,611e618.
Thomas,S.,Legendre,M.,Saunier,S.,Bessieres,B.,Alby,C.,Bonniere,M.,Toutain,A.,Loeuillet,L.,Szymanska,K.,Jossic,F.,Gaillard,D.,Yacoubi,M.T.,MougouZerelli,S.,David,A.,Barthez,M.A.,Ville,Y.,Bole-Feysot,C.,Nitschke,P.,Lyonnet,S.,Munnich,A.,Johnson,C.A.,Encha-Razavi,F.,Cormier-Daire,V.,Thauvin-Robinet,C.,Vekemans,M.,Attie-Bitach,T.,2012.TCTN3 mutations cause Mohr-Majewski syndrome.Am.J.Hum.Genet.91,372e378.
Traboulsi,E.I.,2004.Congenital abnormalities of cranial nerve development:overview,molecular mechanisms,and further evidence of heterogeneity and complexity of syndromes with congenital limitation of eye movements.Trans.Am.Ophthalmol.Soc.102,373e389.
Traeger-Synodinos,J.,2017.Pre-implantation genetic diagnosis.Best Pract.Res.Clin.Obstet.Gynaecol.39,74e88.
Tsurusaki,Y.,Yonezawa,R.,Furuya,M.,Nishimura,G.,Pooh,R.K.,Nakashima,M.,Saitsu,H.,Miyake,N.,Saito,S.,Matsumoto,N.,2014.Whole exome sequencing revealed biallelic IFT122 mutations in a family with CED1 and recurrent pregnancy loss.Clin.Genet.85,592e594.
Tur-Torres,M.H.,Garrido-Gimenez,C.,Alijotas-Reig,J.,2017.Genetics of recurrent miscarriage and fetal loss.Best Pract.Res.Clin.Obstet.Gynaecol.42,11e25.
Valente,E.M.,Logan,C.V.,Mougou-Zerelli,S.,Lee,J.H.,Silhavy,J.L.,Brancati,F.,Iannicelli,M.,Travaglini,L.,Romani,S.,Illi,B.,Adams,M.,Szymanska,K.,Mazzotta,A.,Lee,J.E.,Tolentino,J.C.,Swistun,D.,Salpietro,C.D.,Fede,C.,Gabriel,S.,Russ,C.,Cibulskis,K.,Sougnez,C.,Hildebrandt,F.,Otto,E.A.,Held,S.,Diplas,B.H.,Davis,E.E.,Mikula,M.,Strom,C.M.,Ben-Zeev,B.,Lev,D.,Sagie,T.L.,Michelson,M.,Yaron,Y.,Krause,A.,Boltshauser,E.,Elkhartoufi,N.,Roume,J.,Shalev,S.,Munnich,A.,Saunier,S.,Inglehearn,C.,Saad,A.,Alkindy,A.,Thomas,S.,Vekemans,M.,Dallapiccola,B.,Katsanis,N.,Johnson,C.A.,AttieBitach,T.,Gleeson,J.G.,2010.Mutations in TMEM216 perturb ciliogenesis and cause Joubert,Meckel and related syndromes.Nat.Genet.42,619e625.
van den Berg,M.M.,van Maarle,M.C.,van Wely,M.,Goddijn,M.,2012.Genetics of early miscarriage.Biochim.Biophys.Acta 1822,1951-199.
van den Boogaard,E.,Kaandorp,S.P.,Franssen,M.T.,Mol,B.W.,Leschot,N.J.,Wouters,C.H.,van der Veen,F.,Korevaar,J.C.,Goddijn,M.,2010.Consecutive or non-consecutive recurrent miscarriage:is there any difference in carrier status?Hum.Reprod.25,1411e1414.
van den Veyver,I.B.,Eng,C.M.,2015.Genome-wide sequencing for prenatal detection of fetal single-gene disorders.Cold Spring Harb.Perspect.Med.5,a023077.
Vimercati,A.,Grasso,S.,Abruzzese,M.,Chincoli,A.,de Gennaro,A.,Miccolis,A.,Serio,G.,Selvaggi,L.,Fascilla,F.D.,2012.Correlation between ultrasound diagnosis and autopsy findings of fetal malformations.J.Prenat.Med.6,13e17.
Vora,N.,Powell,B.,Brandt,A.,Strande,N.,Hardisty,E.,Gilmore,K.,Katherine MForeman,A.,Wilhelmsen,K.,Bizon,C.,Reilly,J.,Owen,P.,M Powell,C.,Skinner,D.,Rini,C.,D Lyerly,A.,A Boggess,K.,Weck,K.,Berg,J.,P Evans,J.,2017.Prenatal exome sequencing in anomalous fetuses:new opportunities and challenges.Genet.Med.19,1207e1216.
Walczak-Sztulpa,J.,Eggenschwiler,J.,Osborn,D.,Brown,D.A.,Emma,F.,Klingenberg,C.,Hennekam,R.C.,Torre,G.,Garshasbi,M.,Tzschach,A.,Szczepanska,M.,Krawczynski,M.,Zachwieja,J.,Zwolinska,D.,Beales,P.L.,Ropers,H.H.,Latos-Bielenska,A.,Kuss,A.W.,2010.Cranioectodermal dysplasia,sensenbrenner syndrome,is a ciliopathy caused by mutations in the IFT122gene.Am.J.Hum.Genet.86,949e956.
Wang,Z.,Yang,Z.,Ke,Z.,Yang,S.,Shi,H.,Wang,L.,2009.Mutations in COL1A1 of type I collagen genes in Chinese patients with osteogenesis imperfecta.J.Investig.Med.57,662e667.
Wieacker,P.,Steinhard,J.,2010.The prenatal diagnosis of genetic diseases.Dtsch.Arztebl.Int.107,857e862.
Witters,G.,Van Robays,J.,Willekes,C.,Coumans,A.,Peeters,H.,Gyselaers,W.,Fryns,J.P.,2011.Trisomy 13,18,21,Triploidy and turner syndrome:the 5T's.Look at the hands.Facts Views Vis.Obgyn.3,15e21.
Wright,C.F.,FitzPatrick,D.R.,Firth,H.V.,2018 May.Paediatric genomics:diagnosing rare disease in children.Nat.Rev.Genet.19,325.
Xu,Y.,Shi,Y.,Fu,J.,Yu,M.,Feng,R.,Sang,Q.,Liang,B.,Chen,B.,Qu,R.,Li,B.,Yan,Z.,Mao,X.,Kuang,Y.,Jin,L.,He,L.,Sun,X.,Wang,L.,2016.Mutations in PADI6 cause female infertility characterized by early embryonic arrest.Am.J.Hum.Genet.99,744e752.
Yan,L.,Huang,L.,Xu,L.,Huang,J.,Ma,F.,Zhu,X.,Tang,Y.,Liu,M.,Lian,Y.,Liu,P.,Li,R.,Lu,S.,Tang,F.,Qiao,J.,Xie,X.S.,2015.Live births after simultaneous avoidance of monogenic diseases and chromosome abnormality by nextgeneration sequencing with linkage analyses.Proc.Natl.Acad.Sci.U.S.A.112,15964e15969.
Yang,Y.,Muzny,D.M.,Reid,J.G.,Bainbridge,M.N.,Willis,A.,Ward,P.A.,Braxton,A.,Beuten,J.,Xia,F.,Niu,Z.,Hardison,M.,Person,R.,Bekheirnia,M.R.,Leduc,M.S.,Kirby,A.,Pham,P.,Scull,J.,Wang,M.,Ding,Y.,Plon,S.E.,Lupski,J.R.,Beaudet,A.L.,Gibbs,R.A.,Eng,C.M.,2013.Clinical whole-exome sequencing for the diagnosis of mendelian disorders.N.Engl.J.Med.369,1502e1511.
Yang,Y.,Muzny,D.M.,Xia,F.,Niu,Z.,Person,R.,Ding,Y.,Ward,P.,Braxton,A.,Wang,M.,Buhay,C.,Veeraraghavan,N.,Hawes,A.,Chiang,T.,Leduc,M.,Beuten,J.,Zhang,J.,He,W.,Scull,J.,Willis,A.,Landsverk,M.,Craigen,W.J.,Bekheirnia,M.R.,Stray-Pedersen,A.,Liu,P.,Wen,S.,Alcaraz,W.,Cui,H.,Walkiewicz,M.,Reid,J.,Bainbridge,M.,Patel,A.,Boerwinkle,E.,Beaudet,A.L.,Lupski,J.R.,Plon,S.E.,Gibbs,R.A.,Eng,C.M.,2014.Molecular findings among patients referred for clinical whole-exome sequencing.J.Am.Med.Assoc.312,1870e1879.
Yates,C.L.,Monaghan,K.G.,Copenheaver,D.,Retterer,K.,Scuffins,J.,Kucera,C.R.,Friedman,B.,Richard,G.,Juusola,J.,2017.Whole-exome sequencing on deceased fetuses with ultrasound anomalies:expanding our knowledge of genetic disease during fetal development.Genet.Med.19,1171e1178.