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CENPJ-Related Disorders via the CENPJ Gene

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

Sequencing

Test Code TestIndividual Gene PriceCPT Code Copy CPT Codes
1104 CENPJ$1060.00 81479 Add to Order
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 18 days.

Clinical Sensitivity
This test will detect mutations in less than 5% of patients with a clinical diagnosis of primary microcephaly (Passemard et al. GeneReviews, 2009, www.genetests.org).

Mutations in the CENPJ gene appear to be a rare cause of SCKL syndrome.

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Deletion/Duplication Testing via aCGH

Test Code TestIndividual Gene PriceCPT Code Copy CPT Codes
600 CENPJ$690.00 81479 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 Features
Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that results from hypoplasia of the cerebral cortex.  The hallmark clinical feature of MCPH is a congenital decrease of the head circumference by at least three standard deviations below the population mean for age and sex, that persists throughout the patient’s lifetime.  Although MCPH has been initially characterized by severe microcephaly in the absence of other congenital anomalies (Jackson et al. Am J Hum Genet 63:541-546, 1998), structural anomalies of the central nervous system have been reported in several cases (Passemard et al. Neurology 73:962-969, 2009; Nicholas et al. Nat Genet 42:1010-1014, 2010; Yu et al. Nat Genet 42:1015-1020, 2010; Bacino et al. Am J Med Genet A 158A:622-625, 2012).  Additional features may include a sloping forehead, various degrees of cognitive disabilities, seizures, congenital hearing loss, and short stature.  Brain imaging findings include reduction of the cerebral cortical volume without gross brain malformations with simplification of the gyral cortical pattern, pachygyria with cortical thickening, hypoplasia, lissencephaly, and polymicrogyria (Jackson et al. Am J Hum Genet 71:136-142, 2002).  In MCPH patients, microcephaly is detectable by the 32nd week of gestation and is apparent at birth (Woods et al.  Am J Hum Genet 76:717-728, 2005).  MCPH is panethnic.  However, its incidence is variable and ranges from 1 in 30,000 to 1 in 250,000 living births (Passemard et al. GeneReviews, 2009, www.genetests.org); and is most elevated in populations where consanguineous marriages are broadly practiced (Bundey and Alam. Eur J Hum Genet 1:206-219, 1993).

Seckel syndrome (SCKL) is a rare disorder characterized by prenatal and postnatal growth delays.  Most common clinical features include low birth weight, microcephaly, proportionate short stature and varying degrees of mental retardation.  Additional features include narrow face, large eyes, beak-like protrusion of the nose, malformed ears, small jaws, clinodactyly, dysplasia of the hips and radial dislocation (Majewski and Goecke Am J Med Genet 12:7-21, 1982).
Genetics
MCPH is a genetically heterogeneous disorder.  To date, eight genes (ASPM, WDR62, MCPH1, CEP152, CENPJ, STIL, CDK5RAP2 and CEP135) have been implicated in the disorder (Bond et al. Nat Genet 32:316-320, 2002; Bilgüvar et al.  Nature 467:207-210, 2010; Jackson. Am J Hum Genet 71:136–142, 2002; Guernsey et al. Am J Hum Genet 87:40-51, 2010; Bond et al. Nat Genet 37:353–355, 2005; Kumar et al. Am J Hum Genet 84:286–290, 2009; Hussain et al. Am J Hum Genet 90:871-878, 2012). 

CENPJ mutations account for less than 5% of cases with known mutations (Passemard, GeneReviews. 2009).  Four mutations have been reported in MCPH cases.  These include 2 missense mutations and two small deletions that are predicted to result in truncated proteins.  Mutations have been reported in patients from various populations. 

In addition to small head and various degrees of mental retardation, MCPH patients with CENPJ mutations that have been reported to date presented with facial dysmorphism, developmental delay, joint stiffness, finger deformities and seizures (Bond 2005, Gul et al. J Hum Genet 51:760-764, 2006, Darvish J Med Genet 47:823-828, 2010).

SCKL is a genetically heterogeneous disorder that is inherited in an autosomal recessive manner.  Mutations in five genes (ATR, CENPJ, CEP152, PCNT and RBBP8) have been reported to be involved in SCKL (O'Driscoll et al. Nat Genet 33:497-501, 2003; Al-Dosari et al. J Med Genet 47:411-414, 2010; Kalay et al. Nat Genet 43:23-26, 2011; Griffith et al. Nat Genet 40:232-236, 2008; Qvist et al. PLoS Genet 7(10):e1002310, Epub 2011).  Most mutations are expected to result in truncated proteins.  To date, only one splicing mutation in the CENPJ gene was reported in one consanguineous family (Al-Dosari et al. J Med Genet 47:411-414, 2010).

The CENPJ gene encodes the centromeric protein J, which is involved in several functions including the maintenance of microsome integrity and spindle morphology.
Testing Strategy
This test involves bidirectional Sanger DNA sequencing of all coding exons and splice sites of the CENPJ gene.  The full coding sequence of each exon plus ~ 20 bp of flanking DNA on either side are sequenced.  We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
Patients with head circumference at least three standard deviations below the age and sex mean, with or without central nervous system anomalies, and with a family history consistent with autosomal recessive mode of inheritance and no mutations in the ASPM or WDR62 genes (Passemard et al. Genereviews, 2009; Bacino, 2012).

Patients with features suggestive of SCKL syndrome are also candidates.

Gene

Official Gene Symbol OMIM ID
CENPJ 609279
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Primary Microcephaly, Autosomal Recessive, Sanger Sequencing Panel
Primary Microcephaly, Autosomal Recessive, via the ASPM Gene
Primary Microcephaly, Autosomal Recessive, via the CDK5RAP2 Gene
Primary Microcephaly, Autosomal Recessive, via the MCPH1 Gene
Primary Microcephaly, Autosomal Recessive, via the STIL Gene
Primary Microcephaly, Autosomal Recessive, via the WDR62 Gene

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Al-Dosari et al. Novel CENPJ mutation causes Seckel syndrome J Med Genet 47:411-414, 2010.  PubMed ID: 20522431
  • Bacino et al. WDR62 missense mutation in a consanguineous family with primary microcephaly. Am J Med Genet A 158A:622-625, 2012. PubMed ID: 22308068
  • Bilgüvar et al.  Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.  Nature 467:207-10, 2010. PubMed ID: 20729831
  • Bond et al. ASPM is a major determinant of cerebral cortical size. Nat Genet 32:316-320, 2002. PubMed ID: 12355089
  • Bond et al. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 37:353–355, 2005. PubMed ID: 15793586
  • Bundey and Alam.  A five-year prospective study of the health of children in different ethnic groups, with particular reference to the effect of inbreeding.  Eur J Hum Genet 1:206-219, 1993. PubMed ID: 8044647
  • Darvish et al. A clinical and molecular genetic study of 112 Iranian families with primary microcephaly. J Med Genet 47:823-828, 2010. PubMed ID: 20978018
  • Griffith et al. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet 40:232-236, 2008. PubMed ID: 18157127
  • Guernsey et al.  Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4.  Am J Hum Genet 87:40-51, 2010. PubMed ID: 20598275
  • Gul et al.  A novel deletion mutation in CENPJ gene in a Pakistani family with autosomal recessive primary microcephaly. J Hum Genet 51:760-764, 2006. PubMed ID: 16900296
  • Hussain et al.  A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function.  Am J Hum Genet 90:871-878, 2012. PubMed ID: 22521416
  • Jackson et al. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71:136–142, 2002. PubMed ID: 12046007
  • Jackson et al.  Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71:136–142, 2002. PubMed ID: 12046007
  • Jackson. Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am J Hum Genet 63:541-546, 1998. PubMed ID: 9683597
  • Kalay et al.  CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet 43:23-26, 2011. PubMed ID: 21131973
  • Kumar et al. Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. Am J Hum Genet 84:286-290, 2009. PubMed ID: 19215732
  • Majewski and Goecke.  Studies of microcephalic primordial dwarfism I: approach to a delineation of the Seckel syndrome.  Am J Med Genet 12:7-21, 1982. PubMed ID: 7046443
  • Nicholas et al. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 42:1010-1014, 2010. PubMed ID: 20890279
  • O'Driscoll et al.  A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497-501, 2003. PubMed ID: 12640452
  • Passemard et al. Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations. Neurology 73:962-969, 2009. PubMed ID: 19770472
  • Passemard et al. GeneReviews, 2009
  • Passemard et al. Primary Autosomal Recessive Microcephaly. GeneReviews, 2009. PubMed ID: 20301772
  • Qvist et al.  CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet 7(10):e1002310, Epub 2011. PubMed ID: 21998596
  • Woods et al. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet 76:717-728, 2005. PubMed ID: 15806441
  • Yu et al. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 42:1015-20, 2010. PubMed ID: 20890278
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all 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 for example 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 and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

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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