Microcephaly and Pontocerebellar Hypoplasia 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: MA0701

The Blueprint Genetics Microcephaly and Pontocerebellar Hypoplasia Panel is a 34 gene test for genetic diagnostics of patients with clinical suspicion of microcephaly or pontocerebellar hypoplasias.

Isolated microcephaly is known to have autosomal dominant, autosomal recessive and X-linked inheritance. Nonsyndromic pontocerebellar hypoplasias (PCH) are generally inherited in an autosomal recessive pattern. This panel enables effective differential diagnostics of microcephaly and pontocerebellar hypoplasia. This panel is part of Comprehensive Skeletal / Malformation Syndrome Panel.

About Microcephaly and Pontocerebellar Hypoplasia

Microcephaly is a neurodevelopmental disorder. It is usually defined as a head circumference (HC) more than two (or three) standard deviations below the mean for age and sex and serves as an important neurological indication or warning sign, however uniformity in its definition is lacking. Microcephaly may be congenital or develop in the first few years of life. In general, life expectancy for individuals with microcephaly is reduced and the prognosis for normal brain function is poor. It may stem from a wide variety of conditions that cause abnormal growth of the brain, or from syndromes associated with chromosomal abnormalities. A homozygous mutation in one of the microcephalin genes (XXX, YYY) causes primary microcephaly. Najm type X-linked intellectual deficit (point mutations and deletions in the CASK gene) is a rare cerebellar dysgenesis syndrome associated with microcephaly in most cases. Examples of monogenic syndromes associated with microcephaly are: Smith–Lemli–Opitz syndrome, Seckel syndrome and Cornelia de Lange syndrome.

Nonsyndromic pontocerebellar hypoplasias (PCH) (eight subtypes described, most of which are very rare) are a rare heterogeneous group of diseases characterized by hypoplasia and atrophy and/or early neurodegeneration of the cerebellum and pons. PCH patients of all subtypes present with progressive microencephaly, delayed or absence of cognitive and voluntary motor development, intellectual deficit, spasticity, chorea/dyskinesia, swallowing difficulties and seizures. PCH patients of all subtypes present with progressive microencephaly, delayed or absence of cognitive and voluntary motor development, intellectual deficit, spasticity, chorea/dyskinesia, swallowing difficulties and seizures. The majority of PCH cases encompass mutations in tRNA splicing endonuclease (TSEN genes). Approximately half the cases of PCH subtype 1 are due to mutations in the EXOSC3 gene. Other subtypes include mutations in for example TSEN2 and TSEN54 genes. Diagnosis is made on clinical symptoms and neuroradiological findings (MRI) and can be confirmed by molecular genetic analyses.

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.

Genes in the Microcephaly and Pontocerebellar Hypoplasia Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
AKT3Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndromeAD821
ASPMMicrocephalyAR139153
ATRCutaneous telangiectasia and cancer syndrome, Seckel syndromeAD/AR613
CASKMental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardationXL4380
CDK5RAP2MicrocephalyAR1515
CENPFCiliary dyskinesia -Lethal CiliopathyAR86
CENPJSeckel syndrome, MicrocephalyAR236
CEP63Seckel syndromeAR42
CEP152Seckel syndrome, MicrocephalyAR1317
CEP164NephronophthisisAR78
DYNC1H1Spinal muscular atrophy, Charcot-Marie-Tooth disease, Mental retardationAD3453
DYRK1AMental retardationAD4050
EFTUD2Mandibulofacial dysostosis with microcephaly, Esophageal atresia, syndromicAD1688
EXOSC3Pontocerebellar hypoplasiaAR918
KIF11MicrocephalyAD1758
LIG4Severe combined immunodeficiency with sensitivity to ionizing radiation, LIG4 syndromeAR836
MBD5Mental retardationAD2172
MCPH1MicrocephalyAR1729
MRE11AAtaxia-telangiectasia-like disorder-1AD2538
NDE1Microhydranencephaly, LissencephalyAR1014
NHEJ1Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiationAR813
OPHN1Mental retardation, with cerebellar hypoplasia and distinctive facial appearanceXL1334
PAFAH1B1Lissencephaly, Subcortical laminar heterotopiaAD106165
PCNTMicrocephalic osteodysplastic primordial dwarfismAR3082
PNKPEpileptic encephalopathy, early infantile, Ataxia-oculomotorAR2116
POMT1Muscular dystrophy-dystroglycanopathyAR3181
PQBP1Renpenning syndromeXL817
RARS2Pontocerebellar hypoplasiaAR1730
STILMicrocephalyAR79
TSEN2Pontocerebellar hypoplasiaAR64
TSEN54Pontocerebellar hypoplasiaAR1620
TUBB2B*Polymicrogyria, asymmetricAD1229
VRK1Pontocerebellar hypoplasiaAR68
WDR62MicrocephalyAR2438
  • * 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 microcephaly and pontocerebellar hypoplasia panel that covers classical genes associated with microcephaly and pontocerebellar hypoplasias. 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 Microcephaly and Pontocerebellar Hypoplasia Panel

ICD-10Disease
Q2Microcephaly
Q04.3Pontocerebellar hypoplasias

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.