Fetal Akinesia Deformation Sequence / LMPS / Related Disorder Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

Test code: MA2301

The Blueprint Genetics Fetal Akinesia Deformation Sequence / LMPS / Related Disorder Panel is a 10 gene test for genetic diagnostics of patients with clinical suspicion of fetal akinesia.

Fetal akinesia deformation sequence syndrome (FADS) is a description of a group of abnormalities resulting from fetal akinesia. It is most often inherited as an autosomal recessive trait, but X-linked or dominant inheritance have also been suggested. FADS shows phenotypic overlap with the lethal type of multiple pterygium syndrome LMPS and this panel can be used for differential diagnostics. Fetal akinesia is a major cause of malformations of arthrogryposis. This panel is part of Arthrogryposes Panel and Comprehensive Skeletal / Malformation Syndrome Panel.

About Fetal Akinesia Deformation Sequence / LMPS / Related Disorder

Fetal akinesia deformation sequence syndrome (FADS) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies. It is also known as Pena-Shokeir syndrome type I and arthrogryposis multiplex congenita (AMC) with pulmonary hypoplasia and characterized by multiple joint contractures, facial anomalies and pulmonary hypoplasia. The common feature of this syndrome is decreased fetal activity. Failure of normal deglutition results in polyhydramnios, and a lack of movement of the diaphragm and intercostal muscles leads to pulmonary hypoplasia. The lack of normal fetal movement also leads to a short umbilical cord and multiple joint contractures. Babies may born prematurely, and even when born at term their growth is delayed, they have a short neck and cryptorchidism. About 30% of affected individuals are stillborn and many live born infants survive only a short time due to complications of pulmonary hypoplasia. The syndrome is rare: about 100 cases have been described in the literature. FADS shows phenotypic overlap with the lethal type of multiple pterygium syndrome LMPS. FADS is most often inherited as an autosomal recessive trait, but X-linked or dominant inheritance have also been suggested. Several mutations have been described in FADS and/or LMPS, explaining around 24% of the cases, and involving genes in the motor neuron development and survival, genes encoding components of the neuromuscular junction (NMJ), adult skeletal muscle proteins, and fetal myostructural proteins. The mutations located in genes associated with the NMJ include the subunits of the acetylcholine receptor (AChR): CHRNA1, CHRND and CHRNG and genes signaling with muscle, skeletal receptor tyrosine kinase (MuSK) in the prepatterning process: RAPSN and DOK7. Also, recently a novel lethal homozygous insertion in the gene encoding MUSK was identified and proposed that whereas milder mutations of MUSK cause a congenital myasthenic syndrome (CMS) phenotype, a complete loss is lethal and will cause FADS.

Availability

Results in 3-4 weeks.

Genes in the Fetal Akinesia Deformation Sequence / LMPS / Related Disorder Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
CHRNA1Myasthenic syndrome, congenitalAD/AR1932
CHRNDMyasthenic syndromeAD/AR1219
CHRNEMyasthenic syndromeAD/AR26121
CHRNGMultiple pterygium syndrome, Escobar syndromeAR1129
COLQMyasthenic syndrome, congenitalAR1266
DOK7Myasthenic syndrome, congenitalAR1568
GLE1Lethal congenital contracture syndrome, Arthrogryposis, lethal, with anterior horn cell diseaseAR49
KLHL40Nemaline myopathyAR524
MUSKMyasthenic syndrome, congenitalAR1017
RAPSNMyasthenic syndrome, congenitalAR1857

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.

Blueprint Genetics offers a comprehensive fetal akinesia deformation sequence / LMPS / related disorder panel that covers classical genes associated with fetal akinesia. 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.

Please see our latest validation report showing sensitivity and specificity for SNPs and indels, sequencing depth, % of the nucleotides reached at least 15x coverage etc. If the Panel is not present in the report, data will be published when the Panel becomes available for ordering. 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. All the Panels available for ordering have sensitivity and specificity higher than > 0.99 to detect single nucleotide polymorphisms and a high sensitivity for indels ranging 1-19 bp. 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. Detection limit for Del/Dup analysis varies through the genome from one to six exon Del/Dups depending on exon size, sequencing coverage and sequence content.

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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ICD & CPT codes

CPT codes

SEQ81479
DEL/DUP81479


ICD codes

Commonly used ICD-10 codes when ordering the Fetal Akinesia Deformation Sequence / LMPS / Related Disorder Panel

ICD-10Disease
Q87.8Fetal akinesia

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.