Unsolved Recognizable Syndromes

Some clinically distinctive syndromes have not yet been explained by single gene mutations or CNVs. They are likely heterogeneous and a few tentative implications of genetic causes have been published. Could they involve non-coding elements? Epigenetic mechanisms? Unknown rare teratogens or rare teratogenXgene interactions?

Genetic Disorder

*Dubowitz Syndrome

Hallermann-Streiff Syndrome

Wieddemann-Rautenstrauch Syndrome

Amyoplasia Congenita Disruptive Sequence

Fryns Syndrome

Cervico-Oculo-Acoustic Syndrome (Wildervanck)

Mohr Syndrome (OFD Type II) Poland Sequence Femoral Hypoplasia-Unusual Facies Syndrome Aase Syndrome Acrodystosis Syndrome *Toriello-Carey Syndrome Oculo-Auriculo-Vertebral Spectrum Oromandibular-Limb Hypogenesis Spectrum (overlaps with Mobius syndrome) Congenital Microgastria-Limb Reduction Complex Sternal Malformation-Vascular Dysplasia (PHACES Syndrome) MURCS Association (Mayer-Rokitansky-Küster-Hauser Type 2)

* Dubowitz Syndrome is probably a collection of heterogeneous disorders with phentype overlap.    20% of Toriello-Carey Syndrome patients have a pathogenic CNV, and some may have de novo mutations in DDX3X We should consider a concerted effort to close the diagnostic gap on these specific conditions while we are working on the larger problem of birth defects and malformations. Experts who have patient collections: now is the time to carry out trio whole genome sequencing. Contact me.

Using Whole Genome Sequencing as Aid in the Diagnosis of Genetic Syndromes

Smith's Recognizable Patterns of Human Malformation is the single textbook that all medical geneticists consult first for syndrome diagnosis. It's hard to overstate it's impact in all of Pediatrics. You will find a copy in many OR's - it provides first line information to all the non-geneticists caring for children with complex birth defects.

I first encountered Smith's in 1983 and I still have my 3rd edition copy. I have purchased a copy of every edition since then. It is a touchstone.

But these conditions are hard to master. I have not 'recognized' many of the nearly 340 conditions (excluding clear teratogenic disorders) described in the book even after 30 years of practice. I may have seen them but not recognized it! 

So what happens when you introduce whole genome sequencing as a first line genetic test? Can cWGS rescue the havetobe dysmorphologists among us? Just for fun I tabulated all the conditions from 1983-2013 listed in the TOC of Smith's and then looked up to see which could be properly evaluated by cWGS. [Hint: cWGS can be used to detect SNPs, Indels, CNVs, SVs and repeat expansions. It is not yet validated for somatic variants, but this is really a matter of coverage depth and tissue selected for sequencing.]

Result: I count 297 recognizable conditions in which cWGS can detect genetic variants underlying the disorders - about 88%. Because of remaining unaccounted locus heterogeneity this does not mean that an abnormality will be found in every case, but you will have coverage of the genes already implicated.

So where are the gaps?  There are a few distinctive conditions, e.g. Hallermann-Streiff, that haven't been 'solved' yet.  There are some conditions in which there is evidence that they may not be genetic in origin e.g. amyoplasia. There are some important conditions that result from somatic mutations - not counting them yet, but they will get included when sequencing depth is routinely increased from 30X. Then there are some that the clinical criteria may just be too non-specific to get into a good study. We need to do lots more cases and then reassess those in the future - 100K is not a bad number to target.

Genetic Disorder WGS Inheritance Genes Chromosomal Abnormality Syndromes Down syndrome x Trisomy 18 x Trisomy 13 x Trisomy 8 x Trisomy 9 Mosaic x Triploidy x Deletion 3p x Duplication 3q x Deletion 4p Syndrome x Deletion 4q x Deletion 5p Syndrome x Deletion 9p Syndrome x Duplication 9p Syndrome x Duplication 10q Syndrome x Deletion 11q syndrome x Aniridia-Wilms Tumor Association x Deletion 13q Syndrome x Duplication of 15q x Deletion 18p Syndrome x Deletion 18q Syndrome x Cat-Eye syndrome x XYY x XXY x XXXY and XXXXY x XXX and XXXX Syndromes x XXXXX Syndrome x Turner syndrome; 45X x Deletions, Duplications, and Microduplication Syndromes Identifiable Using Molecular Technology 1p36 Deletion Syndrome x 1q41-q42 Microdeletion Syndrome x 1q43-q44 Microdeletion Syndrome x 2q37 Deletion Syndrome x 3q29 Deletion Syndrome x 9q34 Subtelomeric Deletion Syndrome x 15q24 Microdeletion Syndrome x 16p11.2-12.2 Microdeletion Syndrome x 17q21 Microdeletion Syndrome x 22q13 Deletion Syndrome x Xq Distal Duplication or Disomy x Very Small Stature, Not Skeletal Dysplasia Brachman-De Lange Syndrome x DN,XL NIPBL,RAD21,SMC3,SMC1A,HDAC8 Rubinstein-Taybi Syndrome x DN CREBBP,EP300,DEL16p13.3 Russel-Silver Syndrome x UPD 7 SHORT Syndrome x DN PIK3R1 3-M Syndrome x AR OBSL1,CUL7,CCDC8 Mulibrey Nanism Syndrome x AR TRIM37 Dubowitz Syndrome Bloom Syndrome x AR RCQL3 De Sanctis-Cacchione Syndrome x AR ERCC6 Johanson-Blizzard Syndrome x AR UBR1 Microcephalic Primordial Dwarfing Syndromes; Seckel Syndrome x TRAIP,CEP63,ATR,NSMCE2,DNA2,CENPJ,NIN,CEP152,RBBP8 Hallermann-Streiff Syndrome Moderate Short Stature, Facial, +/- Genital Smith-Lemli-Opitz Syndrome x AR DHCR7 Kabuki Syndrome x DN KMT2D,KDM6A Williams Syndrome x DN DEL7q11.23 Noonan Syndrome x AD NRAS,RIT1,SOS1,RAF1,BRAF,KRAS,PTPN11,SOS2,LZTR1 Costello Syndrome x DN HRAS Cardio-Facio-Cutaneous Syndrome x DN BRAF Aarskog Sydrome x XL FGD1 Robinow Syndrome x AD,AR DVL1,WNT5A,DVL3,ROR2 Opitz G/BBB Syndrome x XL MID1 Opitz-Frias Syndrome x AD SPECC1L Floating Harbor Syndrome x AD SRCAP Senile-Like Appearance Progeria Syndromes x AD,AR LMNA,BANF1 Wieddemann-Rautenstrauch Syndrome Werner Syndrome x AR RECQL2 Cockayne Syndrome x AR ERCC8 Rothmund-Thomson Syndrome x AR RECQL4 Early Overgrowth with Associated Defects Fragile X Syndrome x XL FMR1 Sotos Syndrome x AD, ?AR NSD1,NFIX,?APC2 Weaver Syndrome x AD EZH2 Marshall-Smith Syndrome x AD NFIX Beckwith-Wiedemann Syndrome x AD CDKN1C Simpson-Golabi-Behmel Syndrome x XL GPC3 Unusual Brain and/or Neuromuscular Findings with Associated Defects Amyoplasia Congenita Disruptive Sequence ?nongenetic Distal Arthrogryposis Syndrome x AD highly heterogeneous Pena-Shokeir I Syndrome x AR DOK7,MUSK,RAPSN Cerebro-Oculor-Facio-Skeletal (COFS); Pena-Shokeir II Syndrome x AR ERCC6,ERCC5,ERCC2,ERCC1 Lethal Multiple Pterygium Syndrome x AR CHRNA1,CHRND,CHRNG Neu-Laxova Syndrome x AR PHGDH,PSAT1 Restrictive Dermopathy x AR ZMPSTE24,LMNA Meckel-Gruber Syndrome x AR KIF14,NPHP3,CC2D2A,TMEM67,TMEM216,CEP290,TCTN2,RPGRIP1L,TMEM231,B9D1,MKS1,B9D2 Pallister-Hall  Syndrome x AD GLI3 Gomez-Lopez-Hernandez Syndrome x AD ZIC2 X-linked Hydrocephalus Syndrome x XL L1CAM Hydrolethalus Syndrome x AR HYLS1,KIF7 Walker-Warburg Syndrome x AR POMGNT1,B3GALNT2,POMGNT2,DAG1,GMPPB,ISPD,POMK,FKTN,POMT1,B3GNT1,TMEM5,POMT2,FKRP,LARGE Miller-Dieker Syndrome x DN DEL17p13.3 Nablus Mask-Like Facial Syndrome x DN DEL8q22.1 Smith-Magenis Syndrome x DN DEL17p11.2,RAI1 Pitt-Hopkins Syndrome x AD TCF4 Sjogren-Larsen Syndrome x AR ALDH3A2 Marinesco-Sjogren Syndrome x AR SIL1 Ataxia-Telangiectasia Syndrome x AR ATM Menkes Syndrome x XL ATP7A Angelman Syndrome x DN DEL15q11.2-q13mat,UPD15q11.1-q13pat,UBE3A Prader-Willi Syndrome x DN DEL15q11.2-q13pat,UPD15q11.1-q13mat Cohen Syndrome x AR VPS13B Killian/Teschler-Nicola Syndrome x DN Tetrasomy 12p Fryns Syndrome Matthew-Wood Syndrome (MCOPS9) x AR STRA6 Zellweger Syndrome x AR highly heterogeneous Lowe Syndrome x XL OCRL Freeman-Sheldon Syndrome x AD MYH3 Myoclonic Dystrophy Syndrome x AD DMPK Schwartz-Jampel Syndrome x AR HSPG2 Marden-Walker Syndrome x AD PIEZO2 Schinzel-Giedeon Syndrome x DN SETBP1 Acrocallosal Syndrome x AR KIF7,Joubert syndrome is highly heterogeneous 3C Syndrome x AR,XL WSHC5,CCDC22 Hecht Syndrome x AD MYH8 Facial Defects as Major Feature(s) Moebius Syndrome x AD PLXND1,REV3L,TUBB3 Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome x AD FOXL2,heterogeneous syndromes with blepharophimosis Robin Sequence Cleft Lip Sequence Van der Woude Syndrome x AD IRF6,GRHL3 Fraser Syndrome x AR FRAS1,GRIP1,FREM2 Frontonasal Dysplasia Sequence x AR ALX3,ALX4,ALX1 Branchio-Ocular-Facial Syndrome x AD TFAP2A Donnai-Barrow Syndrome x AR LRP2 CHARGE Syndrome x AD CHD7 Melnick-Fraser Syndrome x AD EYA1 Waardenburg Syndrome x AD PAX3,MITF,SNAI2,EDNRB,EDN3,SOX10 Treacher-Collins Syndrome x AD,AR TCOF1,POLR1C,POLR1D Mandibulofacial Dysostosis with Microcephaly x AD EFTUD2 Marshall Syndrome x AD COL11A1 Cervico-Oculo-Acoustic Syndrome (Wildervanck) Facial-Limb Defects as Major Feature(s) Miller Syndrome x AR DHODH Nager Syndrome x AD SF3B4 Townes-Brocks Syndrome x AD SAL1,DACT1 Laurin-Sandrow Syndrome x AD LMBR1 Oral-Facial-Digital Syndrome x XL OFD1 Mohr Syndrome (OFD Type II) Deletion 22q11 Syndrome x DN DEL22q11,TBX1 Mietens Syndrome (Mietens-Weber) Oculodentodigital Syndrome x AD GJA1 Lenz Microphthalmia Syndrome x XL NAA10,MCOPS are highly heterogeneous Oto-Palato-Digital Syndrome, Type I x XL FLNA Oto-Palato-Digital Syndrome, Type II x XL FLNA Coffin-Lowry Syndrome x XL RPS6KA3 X-linked Alpha Thalassemia/Mental Retardation Syndrome x XL ATRX FG Syndrome x XL MED12,FLNA,CASK Stickler Syndrome x AD COL9A2,COL11A1,COL11A2,COL9A1,COL2A1,COL2A1 Larsen Syndrome x AD FLNB Catel-Manzke Syndrome x AR TGDS Langer-Giedion Syndrome x AD TRPS1,DEL8q24.11-13 Tricho-Rhino-Phalangeal Syndrome x AD TRPS1,DEL8q24.11-13 Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome x AD TP63 Hay-Wells Syndrome of Ectodermal Dysplasia x AD TP63 Roberts Syndrome x AR ESCO2 Limb Defect as Major Feature Grebe Syndrome x AR GDF5 Poland Sequence Ulnar Mammary Syndrome x AD TBX3 Popliteal Web Syndrome x AD IRF6 Escobar Syndrome x AR CHRNG CHILD Syndrome x XLD NSDHL Femoral Hypoplasia-Unusual Facies Syndrome Tibial Aplasia-Ectrodactyly Syndrome x AD DUP17p13.3 Adams-Oliver Syndrome x AR, AD EOGT,ARHGAP31,RBPJ,NOTCH1,DLL4,DOCK6 Holt-Oram Syndrome x AD TBX5 Levy-Hollister Syndrome x AD FGFR3,FGFR2,FGF10 Okihiro Syndrome (Duane Radial Ray Syndrome) x AD SALL4 Fanconi Pancytopenia Syndrome x AR MAD2L2,UBE2T,PHF9,FANCD2,FANCE,XRCC2,XRCC9,FANCC,FANCF,BRCA2,RAD51A,FANCI,SLX4,ERCC4,PALB2,FANCA,RAD51C,BRIP1,FAAP95 Radial Aplasia-Thrombocytopenia Syndrome x AR RBM8A Aase Syndrome Polysyndactyly Syndrome x AD GLI3 Osteochondrodysplasias Achondrogenesis, Type IA and IB x AR TRIP11,SLC26A2 Type II Achondrogenesis-Hypochondrogenesis x AD COL2A1 Fibrochondrogenesis x AR,AD COL11A2,COL11A1 Atelosteogensis, Type I x AD,AR FLNB,SLC26A2 Short Rib-Polydactyly Syndromes x AR DYNC2LI2,IFT172,WDR35,TTC21B,IFT80,TCTEX1D2,EVC2,EVC,WDR19,NEK1,CEP120,WDR60,WDR34,DYNC2H1,KIAA0586,SRTD1,IFT140,IFT52 Thanatophoric Dysplasia Syndrome x DN FGFR3 Jeune Thoracic Dystrophy x AR short rib thoracic dysplasia syndromes Campomelic Dysplasia Syndrome x DN SOX9 Achondroplasia Syndrome x AD FGFR3 Hypochondroplasia Syndrome x AD FGFR3 Pseudoachondroplasia x AD COMP Acromesomelic Dysplasia Syndrome x AR GDF5 Spondyloepiphyseal Dysplasia Congenita Syndrome x AD COL2A1 Kniest Syndrome x AD COL2A1 Dyggve-Melchior-Clausen Syndrome x AR DYM Smith-McCort Dysplasia x AR DYM,RAB33B Kozlowski Spondylometaphyseal Dysplasia Syndrome x AD TRPV4 Metatropic Dysplasia x AD TRPV4 Geleophysic Dysplasia x AR,AD ADAMTSL2,FBN1 Chondrodermal Dysplasia x same as Ellis-Van Creveld Chondrodermal Dysplasia (Ellis-Van Creveld) Syndrome x AR EVC,EVC2 Diastrophic Dysplasia x AR SLC26A2 X-linked Spondyloepiphyseal Dysplasia Syndrome x XLR TRAPPC2 Multiple Epiphyseal Dysplasia Syndrome x AD COL2A1 Schmid Metaphyseal Chondrodysplasia Syndrome x AD COL10A1 McKusick Metaphyseal Chondrodysplasia Syndrome (Cartilage Hair Hypoplasia) X AR RMRP Jansen Metaphyseal Chondrodysplasia Syndrome x AD PTHR1 Conradi-Hunermann Syndrome x XLD EBP Rhizomelic Chondrodysplasia Punctata Syndrome x AR GNPAT,AGPS,PEX7,PEX5 X-linked Hypophosphatemic Rickets x XLD PHEX Kenny Syndrome x AR,AD TBCE,FAM111A Hypophosphatasia Syndrome x AR ALPL Hajdu-Cheney Syndrome x AD NOTCH2 Craniometaphyseal Dysplasia Syndrome x AR GJA1 Frontometaphyseal Dysplasia Syndrome x XL FLNA Pyle Metaphyseal Dysplasia Syndrome x AR SFRP4 Osteochondrodysplasia with Osteopetrosis Osteopetrosis: Autosomal Recessive-Lethal x AR OSTM1,SNX10,CA2,TCIRG1,TNFSF11,CLCN7,PLEKHM1,TNFRSF11A Sclerosteosis Syndrome x AR,AD SOST,LRP4 Lenz-Majewski Hyperostosis Syndrome x AD PTDSS1 Pyknodystosis Syndrome x AR CTSK Cleidocranial Dysostosis Syndrome x AD RUNX2 Yunis-Varon Syndrome x AR FIG4 Craniosynostosis Syndromes Saethre-Chotzen Syndrome x AD TWIST1,FGFR2 Pfeiffer Syndrome x AD FGFR2,FGFR1 Carpenter Syndrome x AR RAB23,MEGF8 Apert Syndrome x AD FGFR2 Crouzon Syndrome x AD FGFR2 FGFR3-Associated Coronal Synostosis Syndrome x AD FGFR3 Curry-Jones Syndrome Somatic SMOH Craniofrontonasal Dysplasia x XLD EFNB1 Greig Cepahlopolysyndactyly x AD GLI3 Atley-Bixler Syndrome x AR FGFR2 Baller-Gerold Syndrome x AR RECQL4 Other Skeletal Dysplasias Multiple Synostosis Syndrome x AD NOG,FGF9,GDF5 Spondylocarpotarsal Synostosis Syndrome x AD FLNB Larsen Syndrome x AD FLNB Multiple Exostoses Syndrome x AD EXT1 Nail-Patella Syndrome x AD LMX1B Meir-Gorlin Syndrome x AR,AD ORC1,ORC4,GMNN,WNT10B,ORC6,CDT1,CDC6 Cantu Syndrome x AD ABCC9 Leri-Weill Dyschondrostenosis Syndrome x AD SHOX,SHOXY Langer Mesomelic Dysplasia x AR SHOX,SHOXY Acrodystosis Syndrome Albright Hereditary Osteodystrophy Syndrome x AD GNAS Desbuquois Dysplasia x AR CANT1,XYLT1 Brachydactyly Syndrome Type E x AD HOXD13 Weill-Marchesani Syndrome x AR ADAMTS10,ADAMTS17,LTBP2,FBN1 Storage Disorders Generalized Gangliosidosis Syndrome, Type I x AR GLB1 Leroy I-Cell Sydrome x AR GNPTAB Hurler Syndrome x AR IDUA Hurler-Scheie Compound Syndrome x AR IDUA Scheie Syndrome x AR IDUA Pseudo-Hurler Polydystrophy x AR GNPTAB Hunter Syndrome x XLR IDS Maroteaux-Lamy Mucopolysaccharidosis x AR ARSB Morquio Syndrome x AR GLB1,GALNS Sanfilippo Syndrome x AR SGSH,NAGLU,HGSNAT Mucopolysaccharidosis Type VII x AR GUSB Connective Tissue Disorders Marfan Syndrome x AD FBN1 Beals Syndrome x AD FBN2 Homocystinuria Syndrome x AR CBS Sprintzen-Goldberg Syndrome x AD SKI Camurati-Englemann Syndrome x AD TGFB1 Ehlers-Danlos Syndrome x AD COL5A1,COL5A2,extensive additional phenotypic and locus heterogeneity Vascular Ehlers-Danlos Syndrome (EDS IV) x AD COL3A1 Loeys-Dietz Syndrome x AD TGFBR2,TGFBR1,SMAD3,TGFB2 Osteogenesis Imperfecta, Type I x AD COL1A1,P3H1,CRTAP,SPARC,COL1A2,BMP1,TMEM38B,IFITM5,OI16,SERPINH1,WNT1,SP7,PPIB,SERPINF1,FKBP10 Osteogenesis Imperfecta, Type II x AD COL1A2 Fibrodysplasia Ossificans Progressiva Syndrome x AD ACVR1 Hamartoses Sturge-Weber Sequence Somatic GNAQ Neurocutaneous Melanosis Sequence Somatic NRAS Linear Sebaceous Nevus Sequence Somatic NRAS,PIK3CA,FGFR3,HRAS Incontinentia Pigmenti Syndrome x XLD IKBKG Hypomelanosis of Ito Syndrome likely heterogeneous somatic mutations Tuerous Sclerosis Syndrome x AD TSC1,TSC2 Neurofibromatosis Syndrome x AD NF1 McCune-Albright Syndrome somatic GNAS Von Hippel-Lindau Syndrome x AD VHL Klippel-Trenaunay Syndrome Somatic PIK3CA,less than 10% cells Macrocephaly-Capillary Malformation Syndrome Somatic PIK3CA Proteus Syndrome Somatic AKT1 Encephalocraniocutaneous Lipomatosis Somatic FGFR1 Maffucci Syndrome Somatic ?IDH1 Peutz-Jeghers Syndrome x AD STK11 Bannayan-Riley-Ruvalcaba Syndrome x AD PTEN Gardner Syndrome x AD APC Osler Hemorrhagic Telangiectasia Syndrome x AD ENG,GDF2,ACVR1 Multiple Endocrine Neoplasia Type 2b x AD RET Gorlin Syndrome x AD PTCH2,PTCH1,SUFU Multiple Lentigenes Syndrome - LEOPARD x AD PTPN11,RAF1,BRAF Goltz Syndrome x XLD PORCN Dyskeratosis Congenita Syndrome x XLR, AR, AD DKC1,TERC,TERT,TERT,NOLA2,TINF2,TINF2,NOLA3,PARN,ACD,ACD,WRAP53,RTEL1,RTEL1 Microphthalmia-Linear Skin Defects Syndrome x XLD HCCS Ectodermal Dysplasias Hypohydrotic Ectodermal Dysplasia Syndrome x XLR EDA Autosomal Recessive Hypohydrotic Ectodermal Dysplasia Syndrome x AR EDAR,EDARADD Rapp-Hodgkin Ectodermal Dysplasia Syndrome x AD TP63 Tricho-Dento-Osseous Syndrome x AD DLX3 Clouston Syndrome x AD GJB6 Cranioectodermal Dysplasia x AR WDR35,IFT122,WDR19,IFT43 GAPO Syndrome x AR ANTXR1 Pachyonychia Congenita Syndrome x AD KRT6A,KRT6B,KRT16,KRT17 Pachydermoperiostosis Syndrome (Touraine-Solente-Gole) x AR HPGD Xeroderma Pigmentosa Syndrome x AR XPA,ERCC3,XPC,ERCC2,ERCC4,ERCC5,DDB2 Senter Syndrome (Senter-KID Syndrome) x AD GJB2 Miscellaneous Syndromes Coffin-Siris Syndrome x AD ARID1A,ARID1B,SMARCE1,SMARCA4,SMARCB1 Borjeson-Forssman-Lehmann Syndrome x XLR PHF6 Alagille Syndrome x AD JAG1,NOTCH2 Melnick-Needles Syndrome x XLD FLNA Bardet-Beidl Syndrome x AR extensive locus heterogeneity, possible digenic inheritance McKusick-Kaufman Syndrome x AR MKS1 Laurence-Moon-Biedl Syndrome x AR PNPLA6 Rieger Syndrome x AD PITX2,FOXC1 Peters' Plus Syndrome x AR B3GLCT Toriello-Carey Syndrome Finlay-Wilson Syndrome x AD KCTD1 Mowat-Wilson x AD ZEB2 Cerebro-Costo-Mandibular Syndrome x AD SNRPB Jarcho-Levin Syndrome (Spondylocostal dysostosis) x AR,AD RIPPLY2,LFNG,MESP2,TBX6,HES7,DLL3 Leprachaunism Syndrome x AR INSR Berardinelli Lipodystophy Syndrome x AR CAV1,AGPAT2,BSCL2,PTRF Distichiasis-Lymphedema Syndrome x AD FOXC2 Vici Syndrome x AR EPG5 Fabry Syndrome x XLR GLA Riley-Day Syndrome x AR IKBKAP Schwachman Syndrome x AR SBDS Wiskott-Aldrich Syndrome x XLR WAS,primary immune deficiencies have extensive locus heterogeneity Chediak-Higashi Syndrome x AR LYST Miscellaneous Sequences Laterality Sequence x XLR,AR,AD ZIC3,MMP21,extensive locus heterogeneity with incomplete penetrance Kartegener Syndrome x AR DRC1,ZMYND10,CCDC39,DNAH5,CCNO,RSPH9,RSPH4A,RSPH3,HEATR2,DNAH11,NME8,SPAG1,LRRC6,DNAI1,ARMC4,DNAJB13,CCDC65,KTU,DNAL1,CILD4,DNAAF4,CILD8,HYDIN,DNAAF1,GAS8,TTC25,CCDC103,DNAI2,CCDC40,CCDC151,CCDC114,DNAAF3,C21ORF59,RSPH1,PIH1D3 Holoproscencephaly Sequence x AD DEL1q41q42,SIX3,GLI2,HPE6,SHH,PTCH1,CDON,ZIC2,HPE8,TGIF1 Meningomyelocele, Anencephaly, Iniencephaly Sequence Occult Spinal Dysraphism Sequence Septo-Optic Dysplasia Sequences x AD LHX4,HESX1,HESX1,HESX1,POU1F1,PROP1,LHX3,OTX2 Athyrotic Hypothyroidism Sequence x AR,AD TSHB,PAX8,NKX2-5,TSHR,CHNG3,THRA DiGeorge Sequence x AD DEL22q11,TBX1 Klippel-Feil Sequence x AD,AR GDF6,GDF3,MEOX1,MYO18B Early Urethral Obstruction Sequence x AD TBX18 Extrophy of Bladder Sequence Extrophy of Cloaca Sequence Urorectal Septum Malformation Sequence Oligohydramnios Sequence x AR ITGA8,FGF20 Sirenomelia Sequence x AD VANGL1 Caudal Dysplasia Sequence x AD VANGL1 Amnion Rupture Sequence Limb-Body Wall Complex Spectra of Defects Oculo-Auriculo-Vertebral Spectrum Oromandibular-Limb Hypogenesis Spectrum Congenital Microgastria-Limb Reduction Complex Sternal Malformation-Vascular Dysplasia Spectrum Miscellaneous Associations VATER Association x AD PTEN,ZIC3 MURCS Association Those tinted blue were present in 1983 and then deprecated in later editions. Purple indicates those added since 1983.