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Ciliopathy Sequencing Panel

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

NGS Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
1056 ACVR2B 81479 Add to Order
AHI1 81407
ANKS6 81479
ARL13B 81479
ARL6 81479
ARMC4 81479
B9D1 81479
B9D2 81479
BBIP1 81479
BBS1 81406
BBS10 81404
BBS12 81479
BBS2 81406
BBS4 81479
BBS5 81479
BBS7 81479
BBS9 81479
C21orf59 81479
C5orf42 81479
CC2D2A 81479
CCDC103 81479
CCDC114 81479
CCDC151 81479
CCDC39 81479
CCDC40 81479
CCDC65 81479
CCNO 81479
CEP164 81479
CEP290 81408
CEP41 81479
CEP83 81479
CFAP53 81479
CFTR 81223
CSPP1 81479
DCDC2 81479
DNAAF1 81479
DNAAF2 81479
DNAAF3 81479
DNAAF4 81479
DNAAF5 81479
DNAH11 81479
DNAH5 81479
DNAH8 81479
DNAI1 81479
DNAI2 81479
DNAL1 81479
DRC1 81479
FOXH1 81479
GDF1 81479
GLIS2 81479
IFT27 81479
INPP5E 81479
INVS 81479
IQCB1 81479
KIF14 81479
KIF7 81479
LEFTY2 81479
LRRC6 81479
LZTFL1 81479
MKKS 81479
MKS1 81479
NEK8 81479
NKX2-5 81479
NME8 81479
NODAL 81479
NPHP1 81406
NPHP3 81479
NPHP4 81479
OFD1 81479
PDE6D 81479
RPGR 81479
RPGRIP1L 81479
RSPH1 81479
RSPH4A 81479
RSPH9 81479
SDCCAG8 81479
SPAG1 81479
TCTN1 81479
TCTN2 81479
TCTN3 81479
TMEM138 81479
TMEM216 81479
TMEM231 81479
TMEM237 81479
TMEM67 81407
TRIM32 81479
TTC21B 81479
TTC8 81479
WDPCP 81479
WDR19 81479
ZIC3 81479
ZMYND10 81479
ZNF423 81479
Full Panel Price* $2990.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
1056 Genes x (93) $2990.00 81223, 81404, 81406(x3), 81407(x2), 81408, 81479(x85) Add to Order
Pricing Comment

If you would like to order a subset of these genes contact us to discuss pricing.

Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Clinical sensitivity for BBS is ~80% (Forsythe and Beales 2015).

Clinical sensitivity for JSRD and MKS is ~ 50% (Parisi and Glass 2013).

Clinical sensitivity for nephronophthisis is approximately 30% overall (Hildebrandt et al. 2009). This NGS test can detect the ~279 kb deletion encompassing the NPHP1 gene if it is present in the homozygous state.

Clinical sensitivity for PCD is ~80% (Zariwala et al. 2013).

Congenital heart defects and heterotaxy are clinically and genetically heterogeneous. The clinical sensitivity for this test is unknown at this time for these disorders.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 ACVR2B$690.00 81479 Add to Order
AHI1$690.00 81479
ARL13B$690.00 81479
ARL6$690.00 81479
B9D1$690.00 81479
BBS1$690.00 81479
BBS10$690.00 81479
BBS12$690.00 81479
BBS2$690.00 81479
BBS4$690.00 81479
BBS5$690.00 81479
BBS7$690.00 81479
BBS9$690.00 81479
C5orf42$690.00 81479
CC2D2A$690.00 81479
CCDC39$690.00 81479
CCDC40$690.00 81479
CEP290$690.00 81479
CEP41$690.00 81479
CFTR$690.00 81222
DNAAF1$690.00 81479
DNAAF2$690.00 81479
DNAAF3$690.00 81479
DNAH11$690.00 81479
DNAH5$690.00 81479
DNAI1$690.00 81479
DNAI2$690.00 81479
DNAL1$690.00 81479
FOXH1$690.00 81479
GDF1$690.00 81479
GLIS2$690.00 81479
INPP5E$690.00 81479
INVS$690.00 81479
IQCB1$690.00 81479
KIF7$690.00 81479
MKKS$690.00 81479
MKS1$690.00 81479
NEK8$690.00 81479
NKX2-5$690.00 81479
NME8$690.00 81479
NODAL$690.00 81479
NPHP1$690.00 81405
NPHP3$690.00 81479
NPHP4$690.00 81479
OFD1$690.00 81479
RPGR$690.00 81479
RPGRIP1L$690.00 81479
RSPH4A$690.00 81479
RSPH9$690.00 81479
SDCCAG8$690.00 81479
TCTN1$690.00 81479
TCTN2$690.00 81479
TMEM138$690.00 81479
TMEM216$690.00 81479
TMEM237$690.00 81479
TMEM67$690.00 81479
TRIM32$690.00 81479
TTC8$690.00 81479
ZIC3$690.00 81479
Full Panel Price* $1670.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
600 Genes x (59) $1670.00 81222, 81405, 81479(x57) Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Approximately 20% of individuals with nephronophthisis have a homozygous deletion encompassing the NPHP1 gene (Hoefele et al 2005; Hildebrandt et al 2009). Gross deletions or duplications that may not be detectable by NGS have been reported in AHI1, ARL6, ARMC4, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, CC2D2A, CCDC40, CEP290, CFTR, DNAAF1, DNAH11, DNAH5, DNAAF4,GDF1, MKS1, NODAL, NPHP1, OFD1, RPGR, SDCCAG8, SPAG1, TMEM67, TRIM32, ZIC3, and ZMYND10 (Human Gene Mutation Database).

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Clinical Features

Joubert (JBTS) Syndrome

Joubert Syndrome and related disorders (JSRD) are marked by hypotonia, abnormal ocular movements, neonatal respiratory difficulties, intellectual disability, hypoplasia of the cerebellar vermis, and malformation of the brainstem. The brain malformations lead to the "molar tooth sign" on cranial MRI, which is pathognomonic for JSRD. Other variable JSRD features include cystic kidneys, nephronophthisis, retinal dystrophy, ocular coloboma, occipital encephalocele, polydactyly, ataxia, and hepatic fibrosis. For more information, see Parisi and Glass 2013; Doherty 2009; Parisi et al. 2007.

Meckel Gruber Syndrome (MKS)

Meckel-Gruber Syndrome (MKS) is a lethal autosomal recessive condition, also marked by brain malformation, cystic renal disease and polydactyly (Alexiev et al. 2006). In MKS, the pathognomonic feature is occipital encephalocele, which is generally identified during routine sonography between 12 and 20 weeks of gestation. MKS is a common cause of prenatal echogenic kidneys (Chaumoitre et al. 2006). Nearly all MKS infants are stillborn or die shortly after birth.

Bardet-Biedl Syndrome

Bardet-Biedl Syndrome (BBS) is an autosomal recessive disorder marked by primary features of obesity, polydactyly, pigmentary retinopathy, hypogonadism, renal anomalies and mental retardation (Elbedour et al. 1994; Sheffield 2010). Secondary features include diabetes, hypertension and congenital heart defects (Green et al. 1989). Although BBS is a rare condition, diagnosis is complicated by the fact that many of the clinical features (i.e. obesity, diabetes, hypertension and developmental delay) are common. In addition, many of the BBS clinical features overlap with those of other well-described developmental disorders, including Meckel-Gruber Syndrome (MKS), Joubert Syndrome (JBTS), Nephronophthisis (NPH), Senior-Loken Syndrome (SLS) and Leber Congenital Amaurosis (LCA). Thus, molecular testing is often useful for confirmation of a clinical diagnosis and to aid in the treatment and management of BBS.

Nephronophthisis and Senior-Loken syndrome

Nephronophthisis (NPH) is the most common genetic cause of progressive renal failure in children and young adults. NPH is characterized by polyuria, growth retardation and progressive deterioration of renal function with normal or slightly reduced kidney size (Hildebrandt et al. 1997; Hildebrandt et al. 2009). Nephronophthisis, when associated with Leber Congenital Amaurosis, is known as Senior-Loken syndrome (SLS) (Otto et al. 2005; Hildebrandt et al. 2009).

Primary Ciliary Dyskinesia

Primary Ciliary Dyskinesia (PCD) is a genetic disorder affecting the function of motile cilia (Leigh et al. 2009). The hallmark features of PCD are neonatal respiratory distress, chronic coughing, and recurrent sinus and/or ear infections; 80-100% of all PCD patients have one or more of these symptoms. In 20-50% of individuals with PCD, the major visceral organs are reversed from their normal positions (situs inversus) (Sutherland and Ware 2009). Kartagener’s syndrome is a condition defined by the symptomatic triad of situs inversus, sinusitis and bronchiectasis. Patients with PCD can also have abnormal orientation of some organs but not others (a condition called situs ambiguus or heterotaxy) (Kennedy et al. 2007). For more information, see GeneReviews (Zariwala et al. 2013).

Heterotaxy, Situs Inversus and Kartagener's syndrome

Primary Ciliary Dyskinesia (PCD) is a genetically heterogeneous disorder affecting the function of motile cilia (Leigh et al. 2009). The hallmark features of PCD are neonatal respiratory distress, chronic coughing, and recurrent sinus and/or ear infections; 80-100% of all PCD patients have one or more of these symptoms. In 20-50% of individuals with PCD, the major visceral organs are reversed from their normal positions, also called situs inversus (Sutherland and Ware 2009). Kartagener’s syndrome is a condition defined by the symptomatic triad of situs inversus, sinusitis and bronchiectasis. Patients with PCD can also have abnormal orientation of some organs but not others, a condition called situs ambiguus or heterotaxy (Kennedy et al. 2007). Heterotaxy syndrome results from a failure to properly establish left-right asymmetry during embryogenesis resulting in an abnormal arrangement of thoracic and/or abdominal visceral organs, including the heart, lungs, liver, spleen, intestines, and stomach. Affected patients frequently have significant morbidity and mortality due to a wide variety of cyanotic congenital heart defects. Common defects besides cardiac malformations include asplenia or polysplenia, left-sided liver, right-sided stomach, gastrointestinal malrotation, and altered lung lobation. Classic heterotaxy, cardiac malformations and visceral laterality defects, has an estimated prevalence of 1:10,000 live births (Lin et al. 2000).

Genetics

The ciliopathy disorders described above have been proposed to represent a single clinical entity, with a spectrum of overlapping symptoms and causative genes.

Joubert and Meckel-Gruber Syndromes

Both JSRD and MKS are genetically heterogeneous; JSRD is known to be caused by pathogenic variants in at least 20 different genes and MKS is caused by pathogenic variants in at least 12 different genes (Parisi and Glass 2013). Most of the genes reported to cause MKS have also been found to cause JSRD, with the exception of B9D2, KIF14, NPHP3, and TTC21B. In addition, all genes reported to cause MKS and JSRD play some role in the structure, function and maintenance of the primary cilia and/or basal body organelle (Hildebrandt et al. 2009). Thus, MKS and JSRD have been proposed to represent a single clinical entity, with a spectrum of overlapping symptoms and causative genes. JSRD and MKS are inherited in an autosomal recessive manner with the exception of OFD1, which is inherited in an X-linked dominant manner.

Bardet-Biedl Syndrome

BBS is a genetically heterogeneous disorder known to be caused by pathogenic variants in at least 19 different genes including ARL6/BBS3, BBIP1/BBS18, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CEP290/BBS14, IFT27/BBS19, LZTFL1/BBS17, MKKS/BBS6, MKS1/BBS13, SDCCAG8/BBS16, TRIM32/BBS11, TTC8/BBS8, and WDPCP/BBS15 (Forsythe and Beales 2015; Leitch et al. 2008; Kim et al. 2010; Otto et al. 2010). TMEM67 is included in this panel as it has been suggested to be a genetic modifier of the BBS phenotype (Leitch 2008). BBS is marked by both intra- and inter-familial phenotypic variability. It has been suggested that BBS has an oligogenic inheritance pattern. Triallelism hypothesis states that three pathogenic alleles in two loci are necessary for BBS. This hypothesis attempts to explain variable expressivity and the observation that several individuals with BBS have been found to have a third rare, possibly pathogenic variant in a second BBS gene (Katsanis et al. 2001; Katsanis. 2004; Leitch et al. 2008). However, others have not found evidence for triallelic inheritance patterns in their cohorts (Smaoui et al. 2006; Abu-Safieh et al. 2012). In the majority of reported cases two pathogenic variants in one gene are sufficient for BBS. However, the severity may be modulated by an additional hypomorphic or loss of function allele(s) at another locus. It is recommended to use an autosomal recessive inheritance model when counseling patients and their families (Forsythe and Beales 2015).

Nephronophthisis and Senior-Loken syndrome

Nephronophthisis and Senior-Loken syndrome are genetically heterogeneous disorders. NPH and SLS are inherited in an autosomal recessive manner. NPH and SLS are caused by pathogenic variants in genes encoding proteins involved in cilia/centrosome structure, maintenance or function (Hildebrandt et al. 2009).

Primary Ciliary Dyskinesia Heterotaxy

Primary Ciliary Dyskinesia is caused by defects in motile cilia. Planar motion cilia (i.e. from the respiratory tract, brain, and reproductive tract) consist of nine microtubule doublets that surround a central core of two microtubules (9+2 configuration). Rotary motion cilia (i.e. those in the embryonal node) lack the central core microtubules (9+0 configuration). All motile cilia have inner and outer dynein arms attached at regular intervals to the nine peripheral microtubule doublets, which serve as molecular motors that drive microtubule sliding. For 9+2 cilia, radial spokes form a signal-transduction scaffold between the peripheral dynein arms and the central-core microtubule pair, giving these cilia their characteristic planar (i.e. forward and backward) motion. Motile cilia are very complex structures composed of roughly 250 proteins (Ferkol & Leigh 2006). To date, defects in over 30 genes have been reported to cause PCD, which is most commonly inherited in an autosomal recessive manner (Zariwala et al. 2013). Rarely, PCD has been found to be inherited in an X-linked manner due to loss-of-function variants in OFD1 or RPGR (Budny et al. 2006; Moore et al 2006). In addition, the INVS/NPHP2 gene has been associated with situs inversus either with or without biliary complications (Schon et al. 2002; Otto et al. 2003). Symptoms of cystic fibrosis can sometimes mimic those of PCD.

Heterotaxy, Situs Inversus and Kartagener's syndrome

Both PCD and heterotaxy are genetically heterogeneous. PCD can be caused by pathogenic variants in at least 30 genes and heterotaxy is caused by pathogenic variants in at least 7 genes (Zariwala et al. 2013). In addition, the INVS/NPHP2 and ANKS6 genes have been associated with situs inversus or heterotaxy, either with or without biliary complications (Schon et al. 2002; Otto et al. 2003; Hoff et al. 2013). Thus, a common thread among all these genes is the association of laterality defects. ACVR2B, FOXH1, LEFTY2, NKX2-5 and NODAL genes are associated with autosomal dominant laterality defects, ZIC3 is associated with X-linked recessive heterotaxy, and ARMC4, ANKS6, CCDC103, CCDC114, CCDC39, CCDC40, CCDC151, CFAP53, C21orf59, DNAAF1, DNAAF2, DNAAF3, DNAAF5 (HEATR2), DNAI1, DNAI2, DNAH5, DNAH11, DNAL1, DNAAF4 (previously called DYX1C1), INVS, LRRC6, NME8, SPAG1, and ZMYND10 are associated with autosomal recessive PCD with and without laterality defects. Heterozygous nonsense and missense variants in GDF1 were identified in individuals with conotruncal heart defects (TOF, DORV, TGA) without visceral laterality defects (Karkera et al. 2007). Two truncating variants in GDF1 were found to cause classic heterotaxy in one Finnish family with heterozygous carriers being asymptomatic (Kaasinen et al. 2010).

See individual gene test descriptions for information on molecular biology of gene products.

Testing Strategy

For this NextGen test, the full coding regions plus ~20 bp of non-coding DNA flanking each exon, are sequenced for each of the ciliopathy genes listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, rare, and undocumented variants are confirmed by Sanger sequencing.

Indications for Test

This test is for patients with symptoms overlapping one or more of the ciliopathy disorders.

Diseases

Name Inheritance OMIM ID
Adolescent Nephronophthisis AR 604387
Atrial Septal Defect With Atrioventricular Conduction Defects AD 108900
Bardet-Biedl Syndrome 1 AR 209900
Bardet-Biedl Syndrome 10 AR 615987
Bardet-Biedl Syndrome 11 AR 615988
Bardet-Biedl Syndrome 12 AR 615989
Bardet-Biedl Syndrome 13 AR 615990
Bardet-Biedl Syndrome 14 AR 615991
Bardet-Biedl Syndrome 15 AR 615992
Bardet-Biedl Syndrome 16 AR 615993
Bardet-Biedl Syndrome 17 AR 615994
Bardet-Biedl Syndrome 18 AR 615995
Bardet-Biedl Syndrome 19 AR 615996
Bardet-Biedl Syndrome 2 AR 615981
Bardet-Biedl Syndrome 3 AR 600151
Bardet-Biedl Syndrome 4 AR 615982
Bardet-Biedl Syndrome 5 AR 615983
Bardet-Biedl Syndrome 6 AR 605231
Bardet-Biedl Syndrome 7 AR 615984
Bardet-Biedl Syndrome 8 AR 615985
Bardet-Biedl Syndrome 9 AR 615986
Ciliary Dyskinesia, Primary, 1 AR 244400
Ciliary Dyskinesia, Primary, 10 AR 612518
Ciliary Dyskinesia, Primary, 11 AR 612649
Ciliary Dyskinesia, Primary, 12 AR 612650
Ciliary Dyskinesia, Primary, 13 AR 613193
Ciliary Dyskinesia, Primary, 14 AR 613807
Ciliary Dyskinesia, Primary, 15 AR 613808
Ciliary Dyskinesia, Primary, 16 AR 614017
Ciliary Dyskinesia, Primary, 17 AR 614679
Ciliary Dyskinesia, Primary, 18 AR 614874
Ciliary Dyskinesia, Primary, 19 AR 614935
Ciliary Dyskinesia, Primary, 2 AR 606763
Ciliary Dyskinesia, Primary, 20 AR 615067
Ciliary Dyskinesia, Primary, 21 AR 615294
Ciliary Dyskinesia, Primary, 22 AR 615444
Ciliary Dyskinesia, Primary, 24 AR 615481
Ciliary Dyskinesia, Primary, 25 AR 615482
Ciliary Dyskinesia, Primary, 26 AR 615500
Ciliary Dyskinesia, Primary, 27 AR 615504
Ciliary Dyskinesia, primary, 29 AR 615872
Ciliary Dyskinesia, Primary, 3 AR 608644
Ciliary Dyskinesia, Primary, 30 AR 616037
Ciliary Dyskinesia, Primary, 6 AR 610852
Ciliary Dyskinesia, Primary, 7 AR 611884
Ciliary Dyskinesia, Primary, 9 AR 612444
Conotruncal Heart Malformations AD 217095
Cranioectodermal Dysplasia 4 AR 614378
Cystic Fibrosis AR 219700
Deafness, Autosomal Recessive 28 AR 609823
Fallot Tetralogy AD 187500
Heterotaxy, Visceral, 4, Autosomal AD 613751
Heterotaxy, Visceral, 5 AD 270100
Heterotaxy, Visceral, X-Linked XL 306955
Hypoplastic Left Heart Syndrome 2 AD 614435
Hypothyroidism, Congenital, Nongoitrous, 5 AD 225250
Infantile Nephronophthisis AR 602088
Joubert Syndrome AR 614615
Joubert Syndrome 1 AR 213300
Joubert Syndrome 10 XL 300804
Joubert syndrome 14 AR 614424
Joubert syndrome 16 AR 614465
Joubert Syndrome 2 AR 608091
Joubert Syndrome 21 AR 615636
Joubert Syndrome 22 AR 615665
Joubert Syndrome 3 AR 608629
Joubert Syndrome 4 AR 609583
Joubert Syndrome 5 AR 610188
Joubert Syndrome 6 AR 610688
Joubert Syndrome 7 AR 611560
Joubert Syndrome 8 AR 612291
Joubert Syndrome 9 AR 612285
Mckusick Kaufman Syndrome AR 236700
Meckel Syndrome 1 AR 249000
Meckel Syndrome 12 AR 616258
Meckel Syndrome 2 AR 603194
Meckel Syndrome 3 AR 607361
Meckel Syndrome 4 AR 611134
Meckel Syndrome 5 AR 611561
Meckel Syndrome 6 AR 612284
Meckel Syndrome 8 AR 613885
Meckel Syndrome 9 AR 614209
Nephronophthisis AR 256100
Nephronophthisis 11 AR 613550
Nephronophthisis 13 AR 614377
Nephronophthisis 18 AR 615862
Nephronophthisis 19 AR 616217
Nephronophthisis 4 AR 606966
Nephronophthisis 7 AR 611498
Nephronophthisis 9 AR 613824
Oral-Facial-Digital Syndrome XL 311200
Renal Dysplasia And Retinal Aplasia AR 266900
Senior-Loken Syndrome 5 AR 609254
Senior-Loken Syndrome 7 AR 613615
Short-Rib Thoracic Dysplasia 5 with or without Polydactyly AR 614376
Transposition Of The Great Arteries, Dextro-Looped 3 AD 613854
Ventricular Septal Defect 3 AD 614432

Related Tests

Name
OFD1-Related Disorders via the OFD1 Gene
Acrocallosal, Fetal Hydrolethalus, and Joubert Syndromes via the KIF7 Gene
Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Autosomal Recessive Limb Girdle Muscular Dystrophy (LGMD) Sequencing Panel
Autosomal Recessive Retinitis Pigmentosa Sequencing Panel with CNV Detection
Bardet-Biedl Syndrome Sequencing Panel
Bardet-Biedl Syndrome via the ARL6/BBS3 Gene
Bardet-Biedl Syndrome via the BBS1 Gene
Bardet-Biedl Syndrome via the BBS10 Gene
Bardet-Biedl Syndrome via the BBS12 Gene
Bardet-Biedl Syndrome via the BBS2 Gene
Bardet-Biedl Syndrome via the BBS4 Gene
Bardet-Biedl Syndrome via the BBS5 Gene
Bardet-Biedl Syndrome via the BBS7 Gene
Bardet-Biedl Syndrome via the BBS9 Gene
Bardet-Biedl Syndrome via the MKKS/BBS6 Gene
Bardet-Biedl Syndrome via the TRIM32/BBS11 Gene
Bardet-Biedl Syndrome via the TTC8/BBS8 Gene
Chronic Pancreatitis Sequencing Panel
Comprehensive Cardiac Arrhythmia Sequencing Panel
Comprehensive Cardiology Sequencing Panel with CNV Detection
Comprehensive Neuromuscular Sequencing Panel
Congenital Hypothyroidism and Thyroid Hormone Resistance Sequencing Panel
Cystic Fibrosis and CF-Related Disorders via the CFTR Gene
Dilated Cardiomyopathy Sequencing Panel with CNV Detection
Disorders of Sex Development and Infertility Sequencing Panel with CNV Detection
Disorders of Sex Development Sequencing Panel with CNV Detection
Female Infertility Sequencing Panel with CNV Detection
Heterotaxy and Conotruncal Heart Defects via the GDF1 Gene
Heterotaxy via the LEFTY2 Gene
Heterotaxy, Situs Inversus and Kartagener's Syndrome Sequencing Panel
Heterotaxy, Visceral 4 (HTX4) via the ACVR2B Gene
Heterotaxy, Visceral 5 (HTX5) via the NODAL Gene
Holoprosencephaly, Autosomal Dominant, Nonsyndromic, Sequencing Panel
Interstitial Lung Disease Sequencing Panel with CNV Detection
Isolated Nonsyndromic Congenital Heart Defects via the NKX2-5 Gene
Isolated Nonsyndromic Congenital Heart Defects via the ZFPM2 (FOG2) Gene
Joubert and Meckel-Gruber Syndromes Sequencing Panel
Joubert and Meckel-Gruber Syndromes via the CC2D2A Gene
Joubert and Meckel-Gruber Syndromes via the CEP290 Gene
Joubert and Meckel-Gruber Syndromes via the RPGRIP1L Gene
Joubert Syndrome via the INPP5E Gene
Joubert Syndrome via the AHI1 Gene
Joubert Syndrome via the ARL13B Gene
Joubert Syndrome via the C5orf42 Gene
Joubert Syndrome via the TMEM138 Gene
Joubert Syndrome via the TMEM216 Gene
Joubert Syndrome via the TMEM237 Gene
Joubert Syndrome, Meckel-Gruber Syndrome, and Nephronophthisis via the TMEM67 Gene
Leber Congenital Amaurosis 10 (LCA10) via the CEP290 Gene
Leber Congenital Amaurosis Sequencing Panel with CNV Detection
Limb-Girdle Muscular Dystrophy (LGMD) Sequencing Panel
Male Infertility Sequencing Panel with CNV Detection
Meckel-Gruber Syndrome / Joubert Syndrome via the TCTN2 Gene
Meckel-Gruber syndrome via the B9D1 Gene
Meckel-Gruber Syndrome via the MKS1 Gene
Nephronophthisis / Senior-Loken Syndrome and Bardet-Biedl Syndrome via the SDCCAG8 Gene
Nephronophthisis and Joubert Syndrome via the NPHP1 Gene
Nephronophthisis and Senior-Loken Syndrome Sequencing Panel
Nephronophthisis and Senior-Loken Syndrome via the CEP164 Gene
Nephronophthisis and Senior-Loken Syndrome via the IQCB1/NPHP5 Gene
Nephronophthisis and Senior-Loken syndrome via the NPHP3 Gene
Nephronophthisis and Situs Inversus via the ANKS6 Gene
Nephronophthisis via the GLIS2 / NPHP7 Gene
Nephronophthisis via the INVS / NPHP2 Gene
Nephronophthisis via the NEK8/NPHP9 Gene
Nephronophthisis via the NPHP4 Gene
Nephrotic Syndrome (NS)/Focal Segmental Glomerulosclerosis (FSGS) Sequencing Panel
Pan Cardiomyopathy Sequencing Panel with CNV Detection
Primary Ciliary Dyskinesia (PCD) via the C21ORF59 Gene
Primary Ciliary Dyskinesia (PCD) via the CCDC103 Gene
Primary Ciliary Dyskinesia (PCD) via the CCDC114 Gene
Primary Ciliary Dyskinesia (PCD) via the CCDC151 Gene
Primary Ciliary Dyskinesia (PCD) via the CCDC39 Gene
Primary Ciliary Dyskinesia (PCD) via the CCDC40 Gene
Primary Ciliary Dyskinesia (PCD) via the CCDC65 Gene
Primary Ciliary Dyskinesia (PCD) via the CCNO Gene
Primary Ciliary Dyskinesia (PCD) via the DNAAF1 / LRRC50 Gene
Primary Ciliary Dyskinesia (PCD) via the DNAAF2 Gene
Primary Ciliary Dyskinesia (PCD) via the DNAAF5 (HEATR2) Gene
Primary Ciliary Dyskinesia (PCD) via the DNAH11 Gene
Primary Ciliary Dyskinesia (PCD) via the DNAH5 Gene
Primary Ciliary Dyskinesia (PCD) via the DNAH8 Gene
Primary Ciliary Dyskinesia (PCD) via the DNAI1 Gene
Primary Ciliary Dyskinesia (PCD) via the DNAI2 Gene
Primary Ciliary Dyskinesia (PCD) via the DNAL1 Gene
Primary Ciliary Dyskinesia (PCD) via the LRRC6 Gene
Primary Ciliary Dyskinesia (PCD) via the NME8 (TXNDC3) Gene
Primary Ciliary Dyskinesia (PCD) via the RPGR Gene
Primary Ciliary Dyskinesia (PCD) via the RSPH1 Gene
Primary Ciliary Dyskinesia (PCD) via the RSPH4A Gene
Primary Ciliary Dyskinesia (PCD) via the RSPH9 Gene
Primary Ciliary Dyskinesia (PCD) via the SPAG1 Gene
Primary Ciliary Dyskinesia (PCD) via the ZMYND10 Gene
Primary Ciliary Dyskinesia (PCD)/Immotile Cilia Syndrome and Cystic Fibrosis Sequencing Panel
Primary Ciliary Dyskinesia (PCD)/Immotile Cilia Syndrome Sequencing Panel
Primary Ciliary Dyskinesia via the DNAAF3 Gene
Retinitis Pigmentosa (includes RPGR ORF15) Sequencing Panel with CNV Detection
Short Rib Skeletal Dysplasia Sequencing Panel
Skeletal Disorders and Joint Problems Sequencing Panel with CNV Detection
Stargardt Disease (STGD) and Macular Dystrophies (includes RPGR ORF15) Sequencing Panel with CNV Detection
Ventricular Septal Defects, Tetralogy of Fallot via the FOXH1 Gene
X-linked Heterotaxy (HTX1) via the ZIC3 Gene
X-Linked Intellectual Disability Sequencing Panel with CNV Detection
X-linked Retinitis Pigmentosa (XLRP) (includes RPGR ORF15) and Choroideremia Sequencing Panel
X-linked Retinitis Pigmentosa (XLRP) via the RPGR (includes ORF15) Gene

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Abu-Safieh L. et al. 2012. European Journal of Human Genetics. 20: 420-7. PubMed ID: 22353939
  • Alexiev B.A. et al. 2006. Archives of Pathology & Laboratory Medicine. 130: 1236-8. PubMed ID: 16879033
  • Budny B. et al. 2006. Human Genetics. 120: 171-8. PubMed ID: 16783569
  • Chaumoitre K. et al. 2006. Ultrasound in Obstetrics & Gynecology. 28: 911-7. PubMed ID: 17094077
  • Doherty D. 2009. Seminars in Pediatric Neurology. 16: 143-54. PubMed ID: 19778711
  • Elbedour K. et al. 1994. American Journal of Medical Genetics. 52: 164-9. PubMed ID: 7802002
  • Forsythe E, Beales PL. 2015. Bardet-Biedl Syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301537
  • Green J.S. et al. 1989. The New England Journal of Medicine. 321: 1002-9. PubMed ID: 2779627
  • Hildebrandt F. et al. 1997. Nature Genetics. 17: 149-53. PubMed ID: 9326933
  • Hildebrandt F. et al. 2009. Journal of the American Society of Nephrology. 20: 23-35. PubMed ID: 19118152
  • Hoefele J. et al. 2005. Human Mutation. 25: 411. PubMed ID: 15776426
  • Hoff S. et al. 2013. Nature Genetics. 45: 951-6. PubMed ID: 23793029
  • Human Gene Mutation Database (Bio-base).
  • Kaasinen E. et al. 2010. Human Molecular Genetics. 19: 2747-53. PubMed ID: 20413652
  • Karkera J.D. et al. 2007. American Journal of Human Genetics. 81: 987-94. PubMed ID: 17924340
  • Katsanis N. 2004. Human Molecular Genetics. 13 Spec No 1: R65-71. PubMed ID: 14976158
  • Katsanis N. et al. 2001. Science. 293: 2256-9. PubMed ID: 11567139
  • Kennedy M.P. et al. 2007. Circulation. 115: 2814-21. PubMed ID: 17515466
  • Kim S.K. et al. 2010. Science. 329: 1337-40. PubMed ID: 20671153
  • Leigh M.W. et al. 2009. Genetics in Medicine. 11: 473-87. PubMed ID: 19606528
  • Leitch C.C. et al. 2008. Nature Genetics. 40: 443-8. PubMed ID: 18327255
  • Lin A.E. et al. 2000. Genetics in Medicine. 2: 157-72. PubMed ID: 11256661
  • Moore A. 2006. Journal of Medical Genetics. 43: 326-33. PubMed ID: 16055928
  • Otto E.A. et al. 2003. Nature Genetics 34: 413–20. PubMed ID: 12872123
  • Otto E.A. et al. 2005. Nature Genetics. 37: 282-8. PubMed ID: 15723066
  • Otto E.A. et al. 2010. Nature Genetics 42: 840–50. PubMed ID: 20835237
  • Parisi M., Glass I. 2013. Joubert Syndrome and Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301500
  • Parisi M.A. et al. 2007. European Journal of Human Genetics. 15: 511-21. PubMed ID: 17377524
  • Schön P. et al. 2002. Human Genetics. 110: 157-65. PubMed ID: 11935322
  • Sheffield V.C. 2010. Transactions of the American Clinical and Climatological Association. 121: 172-81; discussion 181-2. PubMed ID: 20697559
  • Smaoui N. et al. 2006. Investigative Ophthalmology & Visual Science. 47: 3487-95. PubMed ID: 16877420
  • Sutherland M.J., Ware S.M. 2009. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 151C: 307-17. PubMed ID: 19876930
  • Zariwala M.A. et al. 2013. Primary Ciliary Dyskinesia. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301301
Order Kits
TEST METHODS

NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org).  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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