Skeletal Dysplasia Panel, Sequencing and Deletion/Duplication

Last Literature Review: May 2022 Last Update:

Use to assess for causative gene variant(s) in individuals with clinical features of a skeletal dysplasia.

  • Use to assess for causative variant(s) in a fetus with clinical features of a skeletal dysplasia.
  • May also be used as predictive testing in a fetus known to be at risk for a skeletal dysplasia based on family history

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Skeletal dysplasias are a heterogeneous group of more than 400 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. Symptoms are dependent on the specific skeletal dysplasia and include the shortening of the bones of the arms and legs >3 standard deviations below the mean; head circumference >75th percentile, bone abnormalities (e.g., bowed or fractured, irregular, thickened, or thin) undermineralization of bones, abnormal ribs and/or small chest circumference, and polydactyly.

When skeletal dysplasia is suspected prenatally, the fetal skeletal dysplasia panel is the recommended first-line test because providers correctly predict the accurate 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.

Genetics

Genes

See Genes Tested table for genes included in this panel.

Prevalence

Approximately 1/5,000 births 

Etiology

Pathogenic variants in numerous genes with various inheritance patterns (see table below)

Test Interpretation

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing, or NGS) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for the detection of large deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

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, approximately 92% 
    • Diastrophic dysplasia, >90% 

Analytic Sensitivity

For massively parallel sequencing:

Variant ClassAnalytic Sensitivity (PPA) Estimatea (%) and 95% Credibility RegionAnalytic Specificity (NPA)
SNVs>99 (96.9-99.4)>99.9
Deletions 1-10 bpb93.8 (84.3-98.2)>99.9
Insertions 1-10 bpb94.8 (86.8-98.5)>99.9
Exon-levelc deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [Single exon]

>99.9
Exon-levelc duplications83.3 (56.4-96.4) [3 exons or larger]>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA).

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; PPA, positive percent agreement; NPA, negative percent agreement; SNVs, single nucleotide variants

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 and deep intronic variants
    • Deletions/duplications in the upstream regulatory region of SOX9
    • Breakpoints of large deletions/duplications
    • Sequence variants in EVC (NM_153717) exon 1 due to technical limitations of the assay
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Large duplications less than 3 exons in size
    • Noncoding transcripts
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Variants in the chr17:70,119,704-70,119,743 region of SOX9 exon 3
    • Low-level somatic variants

Genes Tested

GeneMIM NumberDisorderInheritance
AGPS603051Rhizomelic chondrodysplasia punctata, type 3AR
ALPL171760

Hypophosphatasia, adult

Odontohypophosphatasia

AD, AR

Hypophosphatasia, infantile

Hypophosphatasia, childhood

AR
ARSL300180Chondrodysplasia punctata, XLXL
CANT1613165

Desbuquois dysplasia 1

Epiphyseal dysplasia, multiple, 7

AR
CCN6603400Progressive pseudorheumatoid dysplasiaAR
CILK1612325

Endocrine-cerebro-osteodysplasia

Epilepsy, juvenile myoclonic, susceptibility to, 10

AR, AD
COL1A1120150

Caffey disease

Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

Ehlers-Danlos syndrome, arthrochalasia type, 1

Osteogenesis imperfecta, types I, II, III, and IV

AD
COL1A2120160

Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2

Osteogenesis imperfecta, types II, III, and IV

Osteoporosis, postmenopausal

AD
Ehlers-Danlos syndrome, cardiac valvular typeAR
COL2A1120140

Achondrogenesis, type II or hypochondrogenesis

Avascular necrosis of the femoral head

Czech dysplasia

Kniest dysplasia

Legg-Calve-Perthes disease

Osteoarthritis with mild chondrodysplasia

Platyspondylic lethal skeletal dysplasia, Torrance type

SMED Strudwick type

Spondyloepiphyseal dysplasia

Spondyloepiphyseal dysplasia, Stanescu type

Stickler syndrome, type 1

Stickler syndrome, type 1 nonsyndrome ocular

AD
COL10A1120110Metaphyseal chondrodysplasia, Schmid typeAD
COL11A1120280

Marshall syndrome

Stickler syndrome, type II

Otospondylomegaepiphyseal dysplasia, autosomal dominant

AD
Fibrochondrogenesis 2AD, AR

Fibrochondrogenesis 1

Otospondylomegaepiphyseal dysplasia, autosomal recessive

AR
COMP600310

Carpal tunnel syndrome 2

Epiphyseal dysplasia, multiple, 1

Pseudoachondroplasia

AD
CRTAP605497Osteogenesis imperfecta, type VIIAR

DDR2

 

191311

 

Warburg-Cinotti syndromeAD
Spondylometaepiphyseal dysplasia, short limb-hand typeAR
DLL3602768Spondylocostal dysostosis 1, ARAR
DYM607461

Dyggve-Melchior-Clausen disease

Smith-McCort dysplasia

AR
DYNC2H1603297Short-rib thoracic dysplasia 3 with or without polydactylyAR, Digenic
EBP300205

Chondrodysplasia punctata 2, X-linked dominant

MEND syndrome

XL
EVC604831Ellis-van Creveld syndromeAR
EVC2607261Weyers acrofacial dysostosisAD
Ellis-van Creveld syndromeAR
FGFR1136350

Hartsfield syndrome

Hypogonadotropic hypogonadism 2 with or without anosmia

Jackson-Weiss syndrome

Osteoglophonic dysplasia​

Pfeiffer syndrome

Trigonocephaly 1

AD
FGFR2176943

Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

Apert syndrome

Beare-Stevenson cutis gyrata syndrome

Bent bone dysplasia syndrome

Craniofacial-skeletal-dermatologic dysplasia

Craniosynostosis, nonspecific

Crouzon syndrome

Jackson-Weiss syndrome

Lacrimoauriculodentodigital (LADD) syndrome

Pfeiffer syndrome

Saethre-Chotzen syndrome

Scaphocephaly and Axenfeld-Rieger anomaly

Scaphocephaly, maxillary retrusion, and mental retardation

AD
FGFR3134934

Achondroplasia

Achondroplasia, severe, with developmental delay and acanthosis nigricans (SADDAN)

Crouzon syndrome with acanthosis nigricans

Hypochondroplasia

Lacrimoauriculodentodigital (LADD) syndrome

Muenke syndrome

Thanatophoric dysplasia, type I

Thanatophoric dysplasia, type II

AD
Captodactyly, tall stature, and hearing loss syndrome (CATSHL)AD, AR
FKBP10607063

Bruck syndrome 1

Osteogenesis imperfecta, type XI

AR
FLNA300017

Cardiac valvular dysplasia, X-linked

Frontometaphyseal dysplasia 1

Heterotopia, periventricular, 1

Intestinal pseudoobstruction, neuronal

Melnick-Needles syndrome

Otopalatodigital syndrome, type I

Otopalatodigital syndrome, type II

Terminal osseous dysplasia

XL
FLNB603381

Atelosteogenesis, type I

Atelosteogenesis, type III

Boomerang dysplasia

Larsen syndrome

AD
Spondylocarpotarsal synostosis syndromeAR
GDF5601146

Brachydactyly, type A2

Brachydactyly, type C

Multiple synostoses syndrome 2

Symphalangism, proximal 1B

AD
Brachydactyly, type A1, CAD, AR

Acromesomelic dysplasia 2A

Acromesomelic dysplasia 2B

AR
GNPAT602744Rhizomelic chondrodysplasia punctata, type 2AR
HSPG2142461

Dyssegmental dysplasia, Silverman-Handmaker type

Schwartz-Jampel syndrome, type 1

AR
IFT80611177Short-rib thoracic dysplasia 2 with or without polydactylyAR
INPPL1600829OpsismodysplasiaAR
LBR600024Greenberg dysplasiaAR
Pelger-Huet anomalyAD
LIFR151443Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndromeAR
NEK1604588Short-rib thoracic dysplasia 6 with or without polydactylyAR, Digenic
Amyotrophic lateral sclerosis, susceptibility to, 24AD
NPR2108961Acromesomelic dysplasia 1, Maroteaux typeAR

Epiphyseal chondrodysplasia, Miura type

Short stature with nonspecific skeletal abnormalities

AD
P3H1610339Osteogenesis imperfecta, type VIIIAR
PCNT605925Microcephalic osteodysplastic primordial dwarfism, type IIAR
PEX7601757

Peroxisome biogenesis disorder 9B

Rhizomelic chondrodysplasia punctata, type 1

AR
POR124015Antley-Bixler syndrome with genital anomalies and disordered steroidogenesisAR
PPIB123841Osteogenesis imperfecta, type IXAR
PTH1R168468

Metaphyseal chondrodysplasia, Murk Jansen type

Failure of tooth eruption, primary

AD

Chondrodysplasia, Blomstrand type

Eiken Syndrome

AR
RUNX2600211

Cleidocranial dysplasia

Cleidocranial dysplasia, forme fruste, dental anomalies only

Cleidocranial dysplasia, forme fruste, with brachydactyly

Metaphyseal dysplasia with maxillary hypoplasia with or without brachydacyly

AD
SERPINH1600943Osteogenesis imperfecta, type XAR
SLC26A2606718

Achondrogenesis, type IB

Atelosteogenesis, type II

De la Chapelle dysplasia

Diastrophic dysplasia

Diastrophic dysplasia, broad bone-platyspondylic variant

Epiphyseal dysplasia multiple, 4

AR
SLC35D1610804Schneckenbecken dysplasiaAR
SMACRCAL1606622Schimke immunoosseous dysplasiaAR
SOX9608160

Campomelic dysplasia

Campomelic dysplasia

Campomelic dysplasia with autosomal sex reversal

AD
TRIP11604505

Achondrogenesis, type IA

Odontochondrodysplasia 1

AR
TRPV4605427

Brachyolmia type 3

Digital arthropathy-brachydactyly, familial

Hereditary motor and sensory neuropathy, type IIc

Metatropic dysplasia

Neuronopathy, distal hereditary motor, type VIII

Parastremmatic, dwarfism

Scapuloperoneal spinal muscular atrophy

SED, Maroteaux type

Spondylometaphyseal dysplasia, Kozlowski type

AD
TTC21B612014Nephronophthisis 12AR, AD
Short-rib thoracic dysplasia 4 with or without polydactylyAR
WDR19608151

Nephronophthisis 13

Senior-Loken syndrome 8

AR
WDR35613602

Short-rib thoracic dysplasia 7 with or without polydactyly

Cranioectodermal dysplasia 2

AR
AD, autosomal dominant; AR, autosomal recessive; XL, X-linked

References

Related Information
Skeletal Dysplasias