Friday, June 30, 2017

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-K├╝ster-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.

Thursday, June 29, 2017

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.