Arthrogryposes Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: MA0501

The Blueprint Genetics Arthrogryposes Panel is a 58 gene test for genetic diagnostics of patients with clinical suspicion of arthrogryposis.

Arthrogryposes are a group of disorders that involve congenital joint contractures. This comprihensive panel includes Fetal Akinesia Deformation Sequence / LMPS / Related Disorder Panel and covers, but is not limited to the disrders covered by the subpanels. This panel enables effective differential diagnostics of arthrogryposes and associated diseases. The Panel is also part of Comprehensive Skeletal / Malformation Syndrome Panel.

About Arthrogryposes

Arthrogryposis (also known as arthrogryposis multiplex congenital, AMC) are characterized by congenital contractures of 2 or more different body areas without a primary neurologic or muscle disease. Children born with joint contractures have abnormal fibrosis of the muscle tissue causing muscle shortening, and therefore are unable to perform passive extension and flexion in the affected joints. Arthrogryposis has been divided into three groups: amyoplasia, distal arthrogryposis, and syndromic. Amyoplasia is characterized by severe joint contractures and muscle weakness, distal arthrogryposis mainly involves the hands and feet, and syndromic group consists of types of arthrogryposis with a primary neurological or muscle disease. 70-80% of the cases of arthrogryposis are caused by neurological abnormalities and most types that have primary neurological or muscle disease result from an underlying genetic syndrome. More than 35 specific genetic disorders associated with arthrogryposis have been described.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Arthrogryposes Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ACTA1 Myopathy AD/AR 50 206
AGRN Myasthenic syndrome, congenital AR 10 10
BIN1 Myopathy, centronuclear AR 7 14
CASK Mental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardation XL 67 87
CFL2 Nemaline myopathy AR 3 5
CHAT Myasthenic syndrome, congenital AR 19 68
CHRNA1 Myasthenic syndrome, congenital AD/AR 24 34
CHRNB1 Myasthenic syndrome AD/AR 7 8
CHRND Myasthenic syndrome AD/AR 17 22
CHRNE Myasthenic syndrome AD/AR 34 126
CHRNG Multiple pterygium syndrome, Escobar syndrome AR 14 31
CHST14 Ehlers-Danlos syndrome, musculocontractural AR 13 21
COL6A2 Epilepsy, progressive myoclonic, Bethlem myopathy, Myosclerosis, congenital, Ullrich congenital muscular dystrophy AD/AR 68 145
COLQ Myasthenic syndrome, congenital AR 16 66
DHCR24 Desmosterolosis AR 6 8
DOK7 Myasthenic syndrome, congenital AR 18 70
DPAGT1 Congenital disorder of glycosylation, Myasthenic syndrome, congenital AR 15 30
ECEL1 Arthrogryposis AR 24 28
EGR2 Neuropathy, Dejerine-Sottas disease, Charcot-Marie-Tooth disease AD/AR 13 20
ERCC5 Xeroderma pigmentosum, Xeroderma pigmentosum/Cockayne syndrome AR 18 51
ERCC6 Xeroderma Pigmentosum-Cockayne Syndrome, De Sanctis-Cacchione syndrome AD/AR 45 92
EXOSC3 Pontocerebellar hypoplasia AR 11 18
FBN2 Congenital contractural arachnodactyly (Beals syndrome) AD 35 87
FHL1* Myopathy with postural muscle atrophy, Emery-Dreifuss muscular dystrophy, Reducing bod myopathy XL 21 59
FKTN Muscular dystrophy-dystroglycanopathy, Dilated cardiomyopathy (DCM), Muscular dystrophy-dystroglycanopathy (limb-girdle) AD/AR 34 53
GBA* Gaucher disease AR 76 459
GBE1 Glycogen storage disease AR 30 71
GFPT1 Myasthenic syndrome, congenital AR 9 41
GLE1 Lethal congenital contracture syndrome, Arthrogryposis, lethal, with anterior horn cell disease AR 7 11
KAT6B Ohdo syndrome, SBBYS variant, Genitopatellar syndrome AD 29 57
KLHL40 Nemaline myopathy AR 8 24
MPZ Neuropathy, Roussy-Levy syndrome, Dejerine-Sottas disease, Charcot-Marie-Tooth disease AD 86 235
MTM1 Myopathy, centronuclear XL 155 289
MUSK Myasthenic syndrome, congenital AR 13 17
MYBPC1 Arthrogryposis, Lethal congenital contractural syndrome AD/AR 5 6
MYH2 Inclusion body myopathy AD 17 22
MYH3 Arthrogryposis AD 18 35
NALCN Neuroaxonal neurodegeneration, infantile, with facial dysmophism, Congenital contractures of the limbs and face, hypotonia, and developmental delay AD/AR 35 39
NEB* Nemaline myopathy AR 68 285
PIEZO2* Marden-Walker syndrome, Distal arthrogryposis AD 26 25
PLOD2 Bruck syndrome, Osteogenesis imperfecta type 3 AR 8 13
PMM2 Congenital disorder of glycosylation AR 58 123
RAPSN Myasthenic syndrome, congenital AR 21 58
RARS2 Pontocerebellar hypoplasia AR 21 33
SCO2 Leigh syndrome, Hypertrophic cardiomyopathy (HCM), Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency, Myopia AR 42 33
SELENON Muscular dystrophy, rigid spine, Myopathy, congenital, with fiber- disproportion AR 27 59
TGFB3 Loeys-Dietz syndrome (Reinhoff syndrome), Arrhythmogenic right ventricular dysplasia AD 13 19
TK2 Mitochondrial DNA depletion syndrome AR 38 45
TNNI2 Arthrogryposis multiplex congenita AD 5 11
TNNT1 Nemaline myopathy AR 2 6
TPM2 CAP myopathy, Nemaline myopathy, Arthrogryposis, distal AD 13 38
TPM3* CAP myopathy, Nemaline myopathy, Myopathy, congenital, with fiber- disproportion AD 19 27
TRPV4 Metatropic dysplasia, Spondyloepiphyseal dysplasia Maroteaux type, Parastremmatic dwarfism, Hereditary motor and sensory neuropathy, Spondylometaphyseal dysplasia Kozlowski type, Spinal muscular atrophy, Charcot-Marie-Tooth disease, Brachyolmia (autosomal dominant type), Familial Digital arthropathy with brachydactyly AD 58 74
TSEN2 Pontocerebellar hypoplasia AR 6 4
TSEN54 Pontocerebellar hypoplasia AR 18 21
VPS33B Arthrogryposis - renal dysfunction - cholestasis AD/AR 12 56
VRK1 Pontocerebellar hypoplasia AR 6 9
ZBTB42 Lethal congenital contracture syndrome AR 1 1

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
CHRNE Chr17:4806454 c.-96C>T NM_000080.3 rs748144899
ERCC6 Chr10:50681659 c.2599-26A>G NM_000124.3 rs4253196
GBE1 Chr3:81542963 c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT NM_000158.3
RAPSN Chr11:47470715 c.-199C>G NM_005055.4
RAPSN Chr11:47470726 c.-210A>G NM_005055.4 rs786200905
TGFB3 Chr14:76425035 c.*495C>T NM_003239.2 rs387906514
TGFB3 Chr14:76447266 c.-30G>A NM_003239.2 rs770828281

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Blueprint Genetics offers a comprehensive Arthrogryposes Panel that covers classical genes associated with arthrogryposis. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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Extra services

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Arthrogryposes Panel

ICD-10 Disease
Q74.3 Arthrogryposis

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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