Skeletal Dysplasia Panel

Skeletal Dysplasia Panel, Sequencing and Deletion/Duplication 2012015
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
  • 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
Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing
  • 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

Testing Strategy

  • When skeletal dysplasia is suspected prenatally, the skeletal dysplasia panel is the recommended first-line test because providers correctly predict the correct skeletal dysplasia diagnosis in only 40% of prenatal cases. 
  • When skeletal dysplasia is suspected postnatally, radiographs and medical genetic consultation are recommended. If a geneticist is confident in the clinical diagnosis, targeted testing for the specific disorder should be performed. If two or more diagnoses are being considered, the skeletal dysplasia panel is recommended.

See Related Tests

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

~1/5,000 births 

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:
    • Thanatophoric dysplasia, 99% 
    • COLA1/2-related osteogenesis imperfecta, >97% 
    • Achondroplasia, 99% 
    • Achondrogenesis type IB, >90% 
    • Campomelic dysplasia, ~92% 
    • Diastrophic dysplasia, >90% 

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

References 
  1. Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet. 1986; 23(4): 328-32. PubMed
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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