Invitae Expanded Skeletal Dysplasia Panel

 

Test description

The Invitae Expanded Skeletal Dysplasia Panel analyzes 109 genes that are associated with skeletal dysplasia (SD) including but not limited to rhizomelic chondrodysplasia, metaphyseal epiphyseal dysplasia, spondylocostal dysostosis, short-rib thoracic dysplasia and mucopolysaccharidosis (MPS). Skeletal dysplasias are genetically heterogeneous disorders characterized by abnormal bone or cartilage growth. The genetic heterogeneity associated with these skeletal conditions can make it difficult to use phenotype as the sole criterion to select a definitive cause. Broad panel testing allows for an efficient evaluation of several potential genes based on a single clinical indication.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. 

Genes tested

ACP5, ADAMTS10, AGPS, ALPL, ANKH, ARSB, ARSE, B3GALT6, B3GAT3, BGN, BMP2, BMPR1B, CFAP410, CANT1, CDC45, CDC6, CDT1, CHST14, CHST3, COL10A1, COL11A1, COL2A1, COL9A1, COL9A2, COL9A3, COMP, CUL7, DDR2, DLL3, DVL1, DVL3, DYM, EBP, EIF2AK3, EVC, EVC2, FBN1, FGFR1, FGFR2, FGFR3, FLNA, FLNB, FN1, GALNS, GDF5, GLB1, GMNN, GNPAT, GNPTAB, GNPTG, GNS, GORAB, GPC6, GUSB, HES7, HGSNAT, HSPG2, HYAL1, ICK, IDS, IDUA, IFT172, IHH, IMPAD1, INPPL1, KAT6B, KIF22, LBR, LEMD3, LFNG, LIFR, LMX1B, MAP3K7, MATN3, MESP2, MGP, MMP13, MMP2, MMP9, NAGLU, NKX3-2, NPR2, OBSL1, ORC1, ORC4, ORC6, PAPSS2, PEX5, PEX7, PTH1R, RIPPLY2, RMRP, ROR2, RSPRY1, RUNX2, SGSH, SH3PXD2B, SLC26A2, SLC39A13, SMAD4, SMARCAL1, SOX9, TBCE, TBX6, TRPV4, WDR35, WISP3, WNT5A, XYLT1

DISORDERS TESTED

Gene

Condition

Inheritance

ACP5 Spondyloenchondrodysplasia with immune dysregulation (SED) AR
ADAMTS10 Weill-Marchesani syndrome (WMS) AR
AGPS Rhizomelic chondrodysplasia punctata type 3 AR
ALPL Hypophosphatasia AD/AR
ANKH Craniometaphyseal dysplasia (CMD)

Chondrocalcinosis

AD

AD

ARSB Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome AR
ARSE Chondrodysplasia punctata XLR
B3GALT6 Spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1)

Ehlers-Danlos syndrome progeroid type 2 (EDSP2)

AR

AR

B3GAT3 Multiple joint dislocations, short stature and craniofacial dysmorphism with or without congential heart defects (JDSCD) AR
BGN Spondyloepimetaphyseal dysplasia (SEMD)

Thoracic aortic aneurysm and dissection (TADD), with or without additional features

XL

XL

BMP2 Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies AD
BMPR1B Acromesomelic dysplasia AR
CANT1 Desbuquois dysplasia AR
CDC45 Meier-Gorlin syndrome AR
CDC6 Meier-Gorlin syndrome 5 (MGORS5), **preliminary evidence AR
CDT1 Meier-Gorlin syndrome AR
CFAP410 Retinal dystrophy

Axial spondylometaphyseal dysplasia (SMDAX)

AR

AR

CHST14 CHST14-congenital disorder of glycosylation, also known as musculocontractural type Ehlers-Danlos syndrome AR
CHST3 Spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD) AR
COL10A1 Metaphyseal chondrodysplasia, Schmid type (MCDS) AD
COL11A1 Fibrochondrogenesis 1 (FBCG1)

Stickler syndrome, type II (STL2)

AR

AD

COL2A1 Achondrogenesis type II

Legg-Calve-Perthes disease

Multiple forms of dysplasia

Stickler syndrome, type I

Spondyloepiphyseal dysplasia congenita

AD

AD

AD

AD

AR

COL9A1 Stickler syndrome, type IV AR
COL9A2 Stickler syndrome

Multiple epiphyseal dysplasia (MED)

AR

AD

COL9A3 Multiple epiphyseal dysplasia (MED)

Stickler syndrome

AD

AR

COMP Multiple epiphyseal dysplasia (MED) 

Pseudoachondroplasia (PSACH)

AD

AD

CUL7 3-M syndrome 1 (3M1) AR
DDR2 Spondylometaepiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL) AR
DLL3 Spondylocostal dysostosis 1 (SCDO1) AR
DVL1 Robinow syndrome (ADRS) AD
DVL3 Robinow syndrome (ADRS) AD
DYM Dyggve-Melchior-Clausen disease (DMC) AR
EBP Chondrodysplasia punctata type II (CDPX2) XLD
EIF2AK3 Wolcott-Rallison syndrome (WRS) AR
EVC Ellis-van Creveld syndrome (EvC) AR
EVC2 Ellis-van Creveld syndrome (EvC)

Weyers acrodental dysostosis (WAD)

AR

AD

FBN1 Marfan syndrome

Stiff skin syndrome

Weill-Marchesani syndrome (WMS)

AD

AD

AD

FGFR1 Kallmann syndrome 2

Craniosynostosis

Hartsfield syndrome

Osteoglophonic dysplasia

AD

AD

AD

AD

FGFR2 Apert syndrome

Crouzon syndrome

Jackson-Weiss syndrome

Pfeiffer syndrome

Beare-Stevenson syndrome

Bent bone dysplasia

AD

AD

AD

AD

AD

AD

FGFR3 Achondroplasia

Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome

Crouzon syndrome with acanthosis nigricans

Hypochondroplasia

Muenke syndrome

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)

Thanatophoric dysplasia

AD

AD

AD

AD

AD

AD

AD

FLNA Periventricular heterotopia with or without Ehlers-Danlos features

Otopalatodigital spectrum disorders

Cardiac valvular dysplasia

XL

XL

XL

FLNB Atelosteogenesis type 1 (AO1)

Larsen syndrome (LRS)

Spondylocarpotarsal synostosis syndrome (SCT)

AD

AD

AR

FN1 Glomerulopathy with fibronectin deposits (GFND)

Spondylometaphyseal dysplasia - Sutcliffe type (SMDCF)

AD

AD

GALNS Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A AR
GDF5 Brachydactyly and symphalangism

Grebe syndrome

Acromesomelic dysplasia

Hunter-Thompson type (AMDH)

Du Pan syndrome

AD

AR

AR

AR

AR

GLB1 GM1 gangliosidosis and mucopolysaccharidosis, type IVB (MPS IVB, also known as Morquio B) AR
GMNN Meier-Gorlin syndrome AD
GNPAT Rhizomelic chondrodysplasia punctata type 2 (RCDP2) AR
GNPTAB Mucolipidosis type II alpha/beta (ML II) 

Mucolipidosis type III alpha/beta (ML III)

AR

AR

GNPTG Mucolipidosis type III gamma (ML III gamma) AR
GNS Mucopolysaccharidosis type IIID (MPS IIID or Sanfilippo D) AR
GORAB Geroderma osteodysplastica (GO) AR
GPC6 Omodysplasia AR
GUSB Mucopolysaccharidosis type VII (MPS VII) AR
HES7 Spondylocostal dysostosis AR
HGSNAT Mucopolysaccharidosis type IIIC (MPS IIIC or Sanfilippo C)

Retinitis pigmentosa (RP)

AR

AR

HSPG2 Schwartz-Jampel syndrome type 1 (SJS1)

Dyssegmental dysplasia, Silverman-Handmaker type (DDSH)

AR

AR

HYAL1 Mucopolysaccharidosis type IX (MPS IX) AR
ICK Endocrine-cerebro-osteodysplasia (ECO) AR
IDS Mucopolysaccharidosis type II (MPS II, also known as Hunter syndrome) XLR
IDUA Mucopolysaccharidosis type I (MPS I) AR
IFT172 Bardet-Biedl syndrome 

Short-rib thoracic dysplasia 10 with or without polydactyly

AR

AR

IHH Brachydactyly type A1 (BDA1)

Acrocapitofemoral dysplasia (ACFD)

AD

AR

IMPAD1 Chondrodysplasia with joint dislocations AR
INPPL1 Opsismodysplasia (OPSMD) AR
KAT6B Genitopatellar syndrome (GPS)

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS)

AD

AD

KIF22 Spondyloepimetaphyseal dysplasia with multiple dislocations (SEMDJL2) AD
LBR Pelger-Huet anomaly

Greenberg dysplasia

AD

AR

LEMD3 Buschke-Ollendorff syndrome (BOS)

Osteopoikilosis, with or without melorheostosis

AD

AD

LFNG Spondylocostal dysostosis AR
LIFR Stuve-Wiedemann syndrome (SWS) AR
LMX1B Nail-patella syndrome (NPS) 

Focal segmental glomerulosclerosis (FSGS)

AD

AD

MAP3K7 Cardiospondylocarpofacial syndrome 

Frontometaphyseal dysplasia

AD

AD

MATN3 Multiple epiphyseal dysplasia (MED) AD
MESP2 Spondylocostal dysostosis AR
MGP Keutel syndrome (KTLS) AR
MMP13 Spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO))

Metaphyseal dysplasia, Spahr type (MDST)

AD

AR

MMP2 Multicentric osteolysis, nodulosis, and arthropathy (MONA) AR
MMP9 Metaphyseal anadysplasia, ** preliminary evidence AR
NAGLU Mucopolysaccharidosis type IIIB (MPS IIIB) AR
NKX3-2 Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) AR
NPR2 Acromesomelic dysplasia, Maroteaux type (AMDM)

Epiphyseal chondrodysplasia, Miura type (ECDM)

AR

AD

OBSL1 3-M syndrome 2 (3M2) AR
ORC1 Meier-Gorlin syndrome 1 (MGORS1) AR
ORC4 Meier-Gorlin syndrome 2 (MGORS2) AR
ORC6 Meier-Gorlin syndrome 3 (MGORS3) AR
PAPSS2 Brachyolmia type 4 (BCYM4) AR
PEX5 Zellweger spectrum disorder (ZSD) 

Rhizomelic chondrodysplasia punctata

AR

AR

PEX7 Rhizomelic chondrodysplasia punctata (RCDP)

Refsum disease

AR

AR

PTH1R Blomstrand chondrodysplasia (BOCD)

Eiken syndrome

Jansen type metaphyseal chondrodysplasia (JMC) 

Primary failure of tooth eruption (PFTE)

AR

AR

AD

AD

RIPPLY2 Spondylocostal dysostosis AR
RMRP Cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders AR
ROR2 Brachydactyly type B1 (BDB1)

Robinow syndrome

AD

AR

RSPRY1 Spondyloepimetaphyseal dysplasia AR
RUNX2 Cleidocranial dysplasia (CCD) AD
SGSH Mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome A AR
SH3PXD2B Frank-Ter Haar syndrome (FTHS) AR
SLC26A2 Achondrogenesis, type IB (ACG1B)

Atelosteogenesis type 2 (AO2)

Diastrophic dysplasia (DTD)

Multiple epiphyseal dysplasia 4 (EDM4)

AR

AR

AR

AR

SLC39A13 Ehlers-Danlos syndrome-like spondylocheirodysplasia (SCD-EDS) AR
SMAD4 Juvenile polyposis syndrome (JPS)

Hereditary hemorrhagic telangiectasia (HHT)

Myhre syndrome

AD

AD

AD

SMARCAL1 Schimke immunoosseous dysplasia (SIOD) AR
SOX9 Campomelic dysplasia AD
TBCE Sanjad-Sakati syndrome (SSS)

Kenney-Caffey syndrome (KCS)

Progressive encephalopathy with amyotrophy and optic atrophy (PEAMO), ** preliminary evidence

AR

AR

AR

TBX6 Spondylocostal dysostosis 5 (SCDO5), ** preliminary evidence AD
TRPV4 Charcot-Marie-Tooth disease type 2C (CMT2C)

Scapuloperoneal spinal muscular atrophy (SPSMA) 

Distal hereditary motor neuropathy 8, also known as distal spinal muscular atrophy (HMN8) 

Skeletal dysplasias

AD

AD

AD
AD

WDR35 autosomal recessive short-rib thoracic dysplasia (SRTD) with or without polydactyly AR
WISP3 Progressive pseudorheumatoid dysplasia (PPRD) AR
WNT5A Robinow syndrome type 1 (ADRS1) AD
XYLT1 Desbuquois dysplasia type 2 AR

AD (autosomal dominant), AR (autosomal recessive), XLD (X-linked dominant), XLR (X-linked recessive), **preliminary evidence (Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test.)

CLINICAL DESCRIPTION

Skeletal dysplasias (SDs) are a complex group of more than 450 conditions with significant clinical and molecular heterogeneity. These conditions are generally characterized by abnormal growth and development of the skeletal system and often involve unusual stature in addition to other skeletal anomalies. Some skeletal dysplasias are lethal prenatally or soon after birth, while lifespan is not affected by other types of SDs. Clinical descriptions of several types of skeletal dysplasia covered by this test are provided below.

FGFR3 Chondrodysplasia

This group of skeletal dysplasias results from pathogenic variants in the FGFR3 gene and includes thanatophoric dysplasia, achondroplasia, hypochondroplasia and in rare cases, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Thanatophoric dysplasia is on the severe end of the FGFR3 disorders spectrum and usually results in early death. It is characterized by macrocephaly, micromelia, bowed femurs, short ribs and narrow thorax, and rhizomelic shortening of the long bones. Achondroplasia is the most common non-lethal skeletal dysplasia. Most children are diagnosed at birth while some patients are identified in early infancy. Achondroplasia is characterized by short stature, macrocephaly, frontal bossing with midface hypoplasia, rhizomelia and distinctive "trident" configuration of the 3rd and 4th fingers. Hypochondroplasia is on the milder end of FGFR3 disorders spectrum and has similar clinical findings as achondroplasia but often without midface hypoplasia.

Collagenopathies

This group of skeletal disorders are caused by pathogenic variants in a group of collagen genes including COL2A1 and COL11A1. Stickler syndrome, spondyloepiphyseal dysplasia congenita and fibrochondrogenesis are examples of collagenopathies and are characterized primarily by skeletal, ocular, facial, and audiological abnormalities. The clinical presentation and severity of these features are highly variable, even within the same family. The most severe clinical presentation includes skeletal anomalies such as micromelia, incomplete bone ossification, platyspondyly, hypoplastic pelvis, and metaphyseal changes and may result in neonatal lethality. At the milder end of the spectrum, individuals may present with short stature, joint pain and stiffness, joint contractures, osteoarthritis, and other skeletal features. Extra-skeletal features are variable and include midface hypoplasia, cleft palate, sensorineural hearing loss, micrognathia, and a prominent abdomen. Ocular features associated with this spectrum include myopia, retinal detachment, and vitreoretinal degenerative cataract.

Short-rib dysplasias

The short-rib dysplasias are ciliopathies characterized by skeletal and visceral anomalies. Affected individuals may present with a severe form of short-rib polydactyly (SRP). Skeletal defects include polysyndactyly, markedly shortened ribs, extreme micromelia, acromesomelic hypomineralization, campomelia, absent ossification, and hypoplastic scapulae. Visceral manifestations include laterality defects, cystic kidneys, ophthalmological problems (nystagmus and retinal dystrophy), nephronophthisis, and cystic liver disease. Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy and short-rib polydactyly syndrome are a few examples of skeletal ciliopathies.

Multiple epiphyseal dysplasia (MED) and Pseudoachondroplasia (PSACH)

Multiple epiphyseal dysplasia (MED) is a disorder of the skeletal system that disturbs ossification of the epiphyses in the major growth centers and ultimately destroys joint cartilage. MED is clinically heterogeneous but symptoms typically present in childhood and include fatigue, pain and stiffness in weight bearing joints, restriction of joint mobility, and at times, a waddling gait. In adulthood, affected individuals experience progressively worsening pain, joint deformity and early-onset osteoarthritis. Affected individuals may also have mild short stature brachydactyly. Pseudoachondroplasia (PSACH) is a severe osteochondrodysplasia affecting skeletal development. Clinical presentation varies, even among families. It is characterized by significant short stature and disproportionately short limbs, which is often evident around 2 years of age. Bowed legs, scoliosis, lumbar lordosis, kyphosis, short fingers, and ligamentous laxity are also frequently reported. Additionally, osteoarthritis of the lower limbs begins in early adulthood, and then progresses to the shoulders and other joints at an earlier age than the general population.

Metaphyseal dysplasia (cartilage-hair hypoplasia)

Metaphyseal dysplasia is characterized by disproportionate short stature, shortened limbs, bowing of the long bones, and a waddling gait. Clinical manifestations typically become evident by the second or third year of life, though there is a high degree of clinical variability between affected individuals. Symptoms may include metaphyseal chondrodysplasia, short stature, hypermobility, sparse hair, ectodermal dysplasia, Hirschsprung disease, anemia, and different degrees of immunodeficiency. The most severe immune presentations include severe combined immunodeficiency (SCID), for which treatment with hematopoietic stem cell transplantation is considered the only curative therapy.

Acromesomelic dysplasia

Acromesomelic dysplasia is a rare group of hereditary skeletal dysplasias characterized by short stature, severely shortened limbs, and hand and foot malformations. The hands and feet are typically the most severely affected. Several subtypes of acromesomelic dysplasia have been described, including the Maroteaux type, which is characterized by severe dwarfism and axial skeletal involvement with wedging of vertebral bodies.

Mesomelic and rhizo-mesomelic dysplasia

Mesomelia is a condition in which the middle parts of limbs (i.e. forearms and lower legs) are abnormally short while rhizomelia is a condition involving the proximal parts of limbs (i.e. upper arms and thighs). Both rhizomelic and mesomelic dysplasia can be observed together in conditions such omodysplasia, type 1 and Robinow syndrome. Omodysplasia, type 1 (OMOD1) is characterized by severe congenital micromelia with shortening and distal tapering of the humeri and femora to give a club-like appearance. Typical facial features include a prominent forehead, frontal bossing, short nose with a depressed broad bridge, short columella, anteverted nostrils, long philtrum, and small chin. Other clinical findings include cryptorchidism, hernias, congenital heart defects, and cognitive delay. Robinow syndrome is characterized by skeletal anomalies, hypoplastic genitalia, dysmorphic features, macrocephaly, increased bone mineral density, and osteosclerosis of the skull and long bones.Skeletal features include mesomelia, brachydactyly, camptodactyly, and bifid thumbs. Affected individuals often have dental anomalies (oligodontia, malocclusion, gingival hypertrophy), and hearing loss.

Bent bone dysplasia

This group of skeletal disorders is characterized by bowing of the short and long bones and includes campomelic dysplasia. Campomelic dysplasia (CD) is characterized by hypoplastic scapulae, shortening and bowing of the long bones, progressive scoliosis, and cervical spine compression. Clinical presentation of CD is variable, and additional features may include Pierre-Robin sequence, congenital laryngotracheomalacia, club foot, and ambiguous genitalia or sex reversal in XY males. Few individuals with CD survive beyond the newborn period. While most cases result from de novo variants, somatic and germline mosaicism have been reported in unaffected parents, as well as transmission from mildly affected parents.

Primordial dwarfism and slender bone dysplasia

This group of skeletal disorders is characterized by slender long bones and includes 3-M syndrome. Patients with 3-M syndrome present with marked prenatal and postnatal growth restriction, proportionate short stature with final height four to six standard deviations below the mean, and normal intelligence. Typical features include short neck, pectus deformities, short thorax, hyperlordosis, characteristic facial features, and joint hypermobility. Characteristic radiologic findings include slender tubular long bones and ribs, foreshortened vertebral bodies, and small pelvis. Gonadal dysfunction, sub-fertility, or infertility have been reported in some affected males.

Lysosomal storage disorders with skeletal involvement

Mucopolysaccharidoses (MPS) are a constellation of diseases caused by the deficiency of a specific lysosomal enzyme involved in the breakdown of complex sugar and protein molecules known as glycosaminoglycans (GAGs, previously called mucopolysaccharides). Specifically, the breakdown of one or more of the following GAGs is disrupted in each MPS: chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS) and/or hyaluronan. Consequently, these substances accumulate in the lysosomes of various tissues resulting in deterioration and degeneration of multiple organs. There is phenotypic variability amongst and within the MPSs, but in general, signs and symptoms of a mucopolysaccharidosis include coarse facial features, progressive cognitive disability, inguinal and/or umbilical hernias, hepatosplenomegaly, cardiac valve dysfunction, recurrent ear and respiratory infections, corneal clouding and skeletal deformities. Central nervous system involvement is seen in types I, II, III and VII. There is a clinical spectrum within each MPS ranging from severe, early onset forms to milder, attenuated forms. Reduced life expectancy is observed in virtually all of the MPSs.

Craniosynostosis

Craniosynostosis is often secondary to pathogenic variants in the FGFR genes. Craniosynostosis is caused by early fusion of the cranial sutures and may involve single or multiple sutures, and may be isolated or occur with additional congenital anomalies.

Inheritance

Skeletal dysplasias can occur in several inheritance patterns including autosomal dominant, autosomal recessive and X-linked.

Clinical sensitivity

The clinical sensitivity of this test is dependent on the individual’s underlying genetic condition. For many rare conditions not listed in the table, the clinical sensitivity is unknown or not well-established.

 

Percent of disorders attributed to pathogenic variants in specific genes

Disorder

% Pathogenic variants in genes

Hypophosphatasia ~95% (ALPL)
Chondrodysplasia punctata 60-75% (ARSE)
Stickler syndrome 10-20% (COL11A1)
  • Achondrogenesis type II
  • Legg-Calve-Perthes disease
  • Multiple forms of dysplasia
  • Stickler syndrome, type I
  • Spondyloepiphyseal dysplasia congenita
>75% (COL2A1)
Chondrodysplasia punctata type II (CDPX2) ~85% (EBP)
  • Apert syndrome
  • Crouzon syndrome
  • Jackson-Weiss syndrome
  • Pfeiffer syndrome
95-100% (FGFR2)
Achondroplasia ~99% (FGFR3)
Periventricular heterotopia with or without Ehlers-Danlos features >99% (FLNA)
Atelosteogenesis type 1 (AO1) >99% (FLNB)
Schwartz-Jampel syndrome type 1 (SJS1) >90% (HSPG2)
Opsismodysplasia (OPSMD) >99% (INPPL1)
Stuve-Wiedemann syndrome (SWS) >60% (LIFR)
Rhizomelic chondrodysplasia punctata (RCDP) >90% (PEX7)
Cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders ~100% (RMRP)
Achondrogenesis, type IB (ACG1B) >90% (SLC26A2)
Campomelic dysplasia >90%
Mucopolysaccharidosis type I (MPS I) 95%-97% (IDUA)
Mucopolysaccharidosis type II (MPS II)
  • 91% (IDS) 
  • 9% of individuals have complex structural rearrangements that are not identified by this assay
Mucopolysaccharidosis type III (MPS III)
  • 60% (SGHS)
  • 30% (NAGLU)
  • 6% (GNS)
  • 4% (HGSNAT)
Ellis-van Creveld syndrome ~50% (EVC and EVC2)

Prevalence

Skeletal dysplasias occur in about 1 in 5,000 live births, or 5% of children born with a congenital condition. The true figure may be higher due to under-diagnosis.

Considerations for testing

This test may be appropriate for individuals with clinical findings suggestive of or consistent with a diagnosis of skeletal dysplasias. These clinical findings may include short stature, disproportionate growth, dysmorphic facial features and skeletal abnormalities.

References

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Assay

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Based on review of current medical guidelines and peer-reviewed publications, our sequence analysis covers clinically important regions of each gene, including coding exons +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. Any variants that fall outside these regions are not analyzed unless otherwise noted. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

The Invitae Expanded Skeletal Dysplasias Panel includes sequence analysis and deletion/duplication analysis of all genes with the exception of the following limitations:

COL11A1 - Deletion/duplication analysis is not offered for exons 16 and 17.
IDS - Detection of complex rearrangements not offered (PMID: 7633410, 20301451)
FN1 - Deletion/duplication analysis is not offered for this gene.