Neuronal Migration Disorder Panel

PLUSbpg-method 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 3–4 weeks. SEQbpg-method 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 3–4 weeks. DEL/DUPbpg-method Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 3–4 weeks.

Test code: MA2601

The Blueprint Genetics Neuronal Migration Disorder Panel is a 47 gene test for genetic diagnostics of patients with clinical suspicion of neuronal migration disorder.

Neuronal migration disorders (NMDs) are classified based on causative genes as well as on brain MRI and neuropathological findings. More than 25 syndromes resulting from abnormal neuronal migration have been described. Among them are syndromes with several different patterns of inheritance; genetic counseling thus differs greatly between syndromes. This panel enables the genetic basis of neuronal migration disorders to be readily determined. This panel covers the smaller Lissencephaly Panel. Neuronal Migration Disorder Panel is part of the Comprehensive Skeletal / Malformation Syndrome panel.

About Neuronal Migration Disorder

Neuronal migration disorders (NMDs) are a group of birth defects caused by the abnormal migration of neurons in the developing brain and nervous system. During development, neurons must migrate from the areas where they are born to the areas where they will settle into their proper neural circuits. The structural abnormalities found in NMDs include schizencephaly, porencephaly, lissencephaly, agyria, macrogyria, polymicrogyria, pachygyria, microgyria, micropolygyria, neuronal heterotopias, agenesis of the corpus callosum, and agenesis of the cranial nerves. Mutations of many genes are involved in neuronal migration disorders, such as DCX in classical lissencephaly spectrum, TUBA1A in microlissencephaly with agenesis of the corpus callosum, and RELN and VLDLR in lissencephaly with cerebellar hypoplasia. Mutations in ARX cause a variety of phenotypes ranging from hydranencephaly or lissencephaly to early-onset epileptic encephalopathies, including Ohtahara syndrome and infantile spasms or intellectual disability with no brain malformations.

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

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Genes in the Neuronal Migration Disorder Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ACTB* Baraitser-Winter syndrome AD 27 26
ACTG1* Deafness, Baraitser-Winter syndrome AD 17 37
ADGRG1 Polymicrogyria, bilateral frontoparietal, Polymicrogyris, bilateral perisylvian AR 22
AKT3 Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome AD 8 21
ARFGEF2 Heterotopia, periventricular AR 5 11
ARX Lissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardation XL 56 80
B3GALNT2 Muscular dystrophy-dystroglycanopathy AR 7 13
CHD7 Isolated gonadotropin-releasing hormone deficiency, CHARGE syndrome AD 128 746
COL4A1 Schizencephaly, Anterior segment dysgenesis with cerebral involvement, Retinal artery tortuosity, Porencephaly, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, Brain small vessel disease AD 27 88
COL4A2 Hemorrhage, intracerebral AD 5 12
COL4A4 Alport syndrome AD/AR 17 170
DCX Lissencephaly, Subcortical laminal heterotopia XL 117 138
DYNC1H1 Spinal muscular atrophy, Charcot-Marie-Tooth disease, Mental retardation AD 34 53
EMX2 Schizencephaly AD 4 6
FH Hereditary leiomyomatosis and renal cell cancer AD 89 161
FKTN Muscular dystrophy-dystroglycanopathy, Dilated cardiomyopathy (DCM), Muscular dystrophy-dystroglycanopathy (limb-girdle) AD/AR 28 51
FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects XL 86 209
GMPPB Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), Limb-girdle muscular dystrophy-dystroglycanopathy AR 13 26
GPSM2 Deafness, Chudley-McCullough syndrome AR 10 11
ISPD Muscular dystrophy-dystroglycanopathy AR 20 42
KIF1BP Goldberg-Shprintzen megacolon syndrome AR 5
KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndrome AR/Digenic 13 39
L1CAM Mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome, Hydrocephalus due to congenital stenosis of aqueduct of Sylvius, Spastic, CRASH syndrome, Corpus callosum, partial agenesis XL 37 286
LAMA2 Muscular dystrophy, congenital merosin-deficient, Schizophrenia AD/AR 72 225
LARGE Muscular dystrophy-dystroglycanopathy AR 15 22
MED12 Ohdo syndrome, Mental retardation, with Marfanoid habitus, FG syndrome, Opitz-Kaveggia syndrome, Lujan-Fryns syndrome XL 17 19
MEF2C Mental retardation AD 25 66
NDE1 Microhydranencephaly, Lissencephaly AR 10 14
NSDHL Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), CK syndrome XL 15 28
PAFAH1B1 Lissencephaly, Subcortical laminar heterotopia AD 106 165
PIK3CA* Cowden syndrome, CLOVES AD 30 44
POMGNT1 Muscular dystrophy-dystroglycanopathy AR 55 73
POMT1 Muscular dystrophy-dystroglycanopathy AR 31 81
POMT2 Muscular dystrophy-dystroglycanopathy AR 28 48
RAB3GAP1 Warburg micro syndrome AR 16 58
RAB3GAP2 Warburg micro syndrome, Martsolf syndrome AR 7 11
RELN Lissencephaly, Epilepsy, familial temporal lobe AD/AR 17 31
SLC12A6 Agenesis of the corpus callosum with peripheral neuropathy (Andermann syndrome) AR 12 17
SRPX2 Rolandic epilepsy, mental retardation, and speech dyspraxia XL 1 3
TMEM5 Muscular dystrophy-dystroglycanopathy AR 8 7
TUBA1A* Lissencephaly AD 33 62
TUBA8 Polymicrogyria with optic nerve hypoplasia AR 1 1
TUBB2B* Polymicrogyria, asymmetric AD 12 29
TUBB3* Fibrosis of extraocular muscles, congenital, Cortical dysplasia, complex, with other brain malformations AD/AR 18 23
VLDLR Cerebellar ataxia, mental retardation, and dysequilibrium syndrome AR 9 21
WDR62 Microcephaly AR 24 38
YWHAE Distal 17p13.3 microdeletion syndrome, Endometrial stromal sarcoma, 17p13.3 microduplication syndrome, Miller-Dieker syndrome AD/AR 11 42

*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.

Blueprint Genetics offers a comprehensive Neuronal Migration Disorder Panel that covers classical genes associated with neuronal migration disorder. 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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ICD & CPT codes

CPT codes

SEQ81479
DEL/DUP81479


ICD codes

Commonly used ICD-10 codes when ordering the Neuronal Migration Disorder Panel

ICD-10 Disease
Q04.3 Neuronal migration disorder

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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