Skeletal Dysplasia Panel
- Confirm diagnosis of a skeletal dysplasia in a symptomatic individual
- Determine the causative gene variant(s) in an affected individual
- Confirm diagnosis of a skeletal dysplasia in a symptomatic fetus
- Determine if a fetus at risk for a skeletal dysplasia based on a positive family history is affected
- Recommended test for a known familial sequence variant previously identified in a family member
- A copy of the family member’s test result documenting the known familial variant is required
Skeletal dysplasias are a heterogeneous group of >350 disorders characterized by abnormal growth of cartilage or bone. Some skeletal dysplasias are detectable prenatally while others are not evident until after birth or in later childhood.
Disease Overview
Symptoms
- Dependent on the specific skeletal dysplasia
- Common symptoms may include:
- Shortening of bones of the arms and legs >3 standard deviations below the mean
- Head circumference >75th percentile
- Bowed or fractured bones
- Irregular, thickened, or thin bones
- Undermineralization of bones
- Abnormal ribs and/or small chest circumference
- Polydactyly
Prevalence
Etiology
Pathogenic variants in numerous genes with various inheritance patterns (see table below)
Test Description
See Genes Tested table for genes included in this panel.
Clinical Sensitivity
- Variable, dependent on specific skeletal dysplasia
- Clinical sensitivity of the most common prenatally detected skeletal dysplasias:
Limitations
- A negative result does not exclude diagnosis of a skeletal dysplasia.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the targeted genes
- Regulatory region variants and deep intronic variants
- Breakpoints of large deletions/duplications
- Deletions/duplications in CANT1, COMP, DDR2, GDF5, HSPG2, PCNT, PTH1R, TRPV4
- Noncoding transcripts
- Exon EVC (NM_153717) 1 is not sequenced due to technical limitations of the assay
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Deletions/duplications less than 1kb in the targeted genes by array
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level mosaic variants
- Single exon deletions/duplications in the following exons:
- ARSE (NM_000047) 9; ARSE (NM_001282631) 1; COL1A1 (NM_000088) 5; COL1A2 (NM_000089) 20, 22; EVC (NM_001306092) 12; PEX7 (NM_000288) 1
Analytical Sensitivity
For massively parallel sequencing:
Variant Class | Analytical Sensitivity (PPA) Estimatea (%) | Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
---|---|---|
SNVs |
99.2 |
96.9-99.4 |
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
Deletions 11-44 bp |
100 |
87.8-100 |
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
Insertions 11-23 bp |
100 |
62.1-100 |
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
Genes Tested
Gene | Alias Symbol(s) | MIM Number | Disorder | Inheritance |
---|---|---|---|---|
AGPS |
ADHAPS, ADAS, ALDHPSY, ADPS, ADAP-S |
603051 |
Rhizomelic chondrodysplasia punctata, type 3 |
AR |
ALPL |
HOPS, TNSALP, TNALP, TNAP |
171760 |
Hypophosphatasia, adult |
AD |
Hypophosphatasia, infantile Hypophosphatasia, childhood |
AR | |||
ARSE |
CDPX, CDPX1 |
300180 |
Chondrodysplasia punctata 1, XL |
XL |
CANT1 |
SHAPY, SCAN-1 |
613165 |
Desbuquois dysplasia 1 |
AR |
COL1A1 |
OI4 |
120150 |
Caffey disease Osteogenesis imperfecta, types I, II, III, and IV |
AD |
COL1A2 |
OI4 |
120160 |
Osteogenesis imperfecta, types II, III, and IV |
AD |
COL2A1 |
SEDC, AOM, STL1 |
120140 |
Platyspondylic lethal skeletal dysplasia, Torrance type Kniest dysplasia Spondyloepiphyseal dysplasia congenita Spondyloepimetaphyseal dysplasia, Strudwick type Achondrogenesis, type II Spondyloperipheral dysplasia Czech dysplasia Spondyloepiphyseal dysplasia, Stanescu type |
AD |
COMP |
PSACH, EDM1, EPD1, MED, THBS5 |
600310 |
Epiphyseal dysplasia, multiple, 1 Pseudoachondroplasia |
AD |
CRTAP |
CASP, LEPREL3, P3H5 |
605497 |
Osteogenesis imperfecta, type VII |
AR |
DDR2 |
TYRO10, NTRKR3, TKT |
191311 |
Spondylometaepiphyseal dysplasia, short limb-hand type |
AR |
DLL3 |
SCDO1 |
602768 |
Spondylocostal dysostosis 1, AR |
AR |
DYNC2H1 |
DNCH2, hdhc11, DHC2, DHC1b, DYH1B |
603297 |
Short-rib thoracic dysplasia 3 with or without polydactyly |
AR |
EBP |
CDPX2, CPX, CPXD, CHO2 |
300205 |
Chondrodysplasia punctata 2, X-linked dominant |
XL |
EVC |
DWF-1 |
604831 |
Ellis-Van Creveld syndrome |
AR |
EVC2 |
LBN |
607261 |
Ellis-Van Creveld syndrome |
AR |
FGFR1 |
FLT2, KAL2, H2, H3, H4, H5, CEK, FLG, BFGFR, N-SAM, CD331 |
136350 |
Osteoglophonic dysplasia Trigonocephaly 1 |
AD |
FGFR2 |
KGFR, BEK, CFD1, JWS, CEK3, TK14, TK25, ECT1, K-SAM, CD332 |
176943 |
Lacrimoauriculodentodigital syndrome Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis Bent bone dysplasia syndrome |
AD |
FGFR3 |
ACH, CEK2, JTK4, CD333 |
134934 |
Achondroplasia Hypochondroplasia Lacrimoauriculodentodigital syndrome Thanatophoric dysplasia, type I Thanatophoric dysplasia, type II Achondroplasia, severe, with developmental delay and acanthosis nigricans |
AD |
FKBP10 |
hFKBP65, FLJ22041, FKBP6, FLJ20683, FLJ23833 |
607063 |
Bruck syndrome 1 Osteogenesis imperfecta, type XI |
AR |
FLNA |
FLN1, FLN, OPD2, OPD1, ABP-280 |
300017 |
Terminal osseous dysplasia Otopalatodigital syndrome, type II Frontometaphyseal dysplasia 1 Otopalatodigital syndrome, type I |
XL |
FLNB |
FLN1L, LRS1, TAP, TABP, ABP-278, FH1 |
603381 |
Atelosteogenesis, type I Atelosteogenesis, type III Boomerang dysplasia Larsen syndrome |
AD |
Spondylocarpotarsal synostosis syndrome |
AR |
|||
GDF5 |
CDMP1, BMP14 |
601146 |
Chondrodysplasia, Grebe type Acromesomelic dysplasia, Hunter-Thompson type |
AR |
GNPAT |
DHAPAT, DAPAT, DAP-AT |
602744 |
Rhizomelic chondrodysplasia punctata, type 2 |
AR |
HSPG2 |
SJS1, perlecan, PRCAN |
142461 |
Dyssegmental dysplasia, Silverman-Handmaker type Schwartz-Jampel syndrome, type 1 |
AR |
ICK |
MRK, LCK2, KIAA0936, MGC46090 |
612325 |
Endocrine cerebro-osteodysplasia |
AR |
IFT80 |
WDR56, KIAA1374 |
611177 |
Short-rib thoracic dysplasia 2 with or without polydactyly |
AR |
LBR |
DHCR14B, TDRD18 |
600024 |
Greenberg dysplasia |
AR |
LIFR |
CD118 |
151443 |
Stuve-Wiedemann syndrome |
AR |
NEK1 |
NY-REN-55, KIAA1901 |
604588 |
Short-rib thoracic dysplasia 6 with or without polydactyly |
AR |
P3H1 |
LEPRE1, GROS1, LEPRECAN, MGC117314 |
610339 |
Osteogenesis imperfecta, type VIII |
AR |
PCNT |
PCNT2, KEN, KIAA0402, PCN, PCNTB, SCKL4 |
605925 |
Microcephalic osteodysplastic primordial dwarfism, type II |
AR |
PEX7 |
PTS2R, RD |
601757 |
Rhizomelic chondrodysplasia punctata, type 1 |
AR |
POR |
CYPOR, FLJ26468 |
124015 |
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis |
AR |
PPIB |
CYPB, OI9, PPIase, B, CYP-S1, SCYLP |
123841 |
Osteogenesis imperfecta, type IX |
AR |
PTH1R |
PTHR, PTHR1 |
168468 |
Metaphyseal chondrodysplasia, Jansen type |
AD |
Chondrodysplasia, Blomstrand type Eiken Syndrome |
AR |
|||
RUNX2 |
CCD, CBFA1, CCD1, AML3, PEBP2A1, PEBP2aA1 |
600211 |
Cleidocranial dysplasia |
AD |
SERPINH1 |
CBP1, CBP2, SERPINH2, HSP47, colligen |
600943 |
Osteogenesis imperfecta, type X |
AR |
SLC26A2 |
DTD, DTDST |
606718 |
Diastrophic dysplasia Atelosteogenesis, type II Achondrogenesis, type IB |
AR |
SLC35D1 |
UGTREL7, KIAA0260 |
610804 |
Schneckenbecken dysplasia |
AR |
SOX9 |
CMD1, CMPD1, SRA1 |
608160 |
Campomelic dysplasia |
AD |
TRIP11 |
CEV14, Trip230, GMAP-210, GMAP210 |
604505 |
Achondrogenesis, type IA |
AR |
TRPV4 |
OTRPC4, TRP12, VROAC, VRL-2, VR-OAC, CMT2C |
605427 |
Metatropic dysplasia Parastremmatic dwarfism Spondyloepiphyseal dysplasia, Maroteaux type Spondylometaphyseal dysplasia, Kozlowski type |
AD |
TTC21B |
FLJ11457, JBTS11, NPHP12, IFT139B, THM1 |
612014 |
Short-rib thoracic dysplasia 4 with or without polydactyly |
AR |
WDR19 |
Pwdmp, KIAA1638, FLJ23127, ORF26, DYF-2, Oseg6, IFT144, NPHP13 |
608151 |
Short-rib thoracic dysplasia 5 with or without polydactyly |
AR |
WDR35 |
MGC33196, KIAA1336, IFT121, IFTA1 |
613602 |
Short-rib thoracic dysplasia 7 with or without polydactyly |
AR |
AD, autosomal dominant; AR, autosomal recessive; XL, X-linked |
- Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet. 1986; 23(4): 328-32. PubMed
- Chen CP, Chern SR, Shih JC, Wang W, Yeh LF, Chang TY, Tzen CY. Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diagn. 2001; 21(2): 89-95. PubMed
- van Dijk FS, Byers PH, Dalgleish R, Malfait F, Maugeri A, Rohrbach M, Symoens S, Sistermans EA, Pals G. EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta. Eur J Hum Genet. 2012; 20(1): 11-9. PubMed
- Bellus GA, Hefferon TW, de Luna RI, Hecht JT, Horton WA, Machado M, Kaitila I, McIntosh I, Francomano CA. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet. 1995; 56(2): 368-73. PubMed
- Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001; 17(3): 159-71. PubMed
- Olney PN, Kean LS, Graham D, Elsas LJ, May KM. Campomelic syndrome and deletion of SOX9. Am J Med Genet. 1999; 84(1): 20-4. PubMed
- Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med. 2009; 11(2): 127-33. PubMed
Last Update: June 2019
Testing Strategy
See Related Tests