DNA icon

Microcephaly, Seizures and Developmental Delay via the PNKP Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
PNKP 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4217PNKP81479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Eric Bend, PhD

Clinical Features and Genetics

Clinical Features

Microcephaly with early-onset, intractable seizures and developmental delay (MCSZ) is an infantile onset seizure disorder. The key features of MCSZ are microcephaly, infantile onset seizures, developmental delay, and variable behavior problems (Shen et al. 2010). MRIs of MCSZ patients show clear microcephaly, but no neuronal migration defects or other brain morphology abnormalities. The initial report of MCSZ did not find any progressive neurological symptoms in any of the patients. However, a more recent account describes siblings with microcephaly, febrile seizures, severe intellectual disability, and ataxia (Poulton et al. 2013). These patients exhibited progressive decline of motor skills which resulted in the patients being wheelchair bound. MRI revealed microcephaly as well as generalized atrophy. Other neurological symptoms included paresis of the arms and legs, contractures, hypotonia, muscular atrophy, and loss of reflexes. Therefore, the clinical spectrum of MCSZ may tentatively be expanded to include patients with progressive neurodegeneration.


MCSZ is inherited in an autosomal recessive manner and is caused by mutations in the PNKP gene. Missense and frameshift variants in PNKP have been reported in patients with MCSZ (Shen et al. 2010; Poulton et al. 2013).

PNKP encodes a polynucleotide 5'-kinase and 3'-phosphatase. PNKP plays a key role in DNA end processing during single-strand and double-strand break repair. In vitro studies show that cells carrying PNKP variants have reduced levels of DNA strand break repair following irradiation (Reynolds et al. 2012). Reported PNKP variants result in reduction of overall PNKP levels. PNKP is expressed in all cell types, but as all reported phenotypes are neurological it is proposed that neurons are hypersensitive to the loss of this enzyme (Shen et al. 2010).

Clinical Sensitivity - Sequencing with CNV PG-Select

Currently there are no large scale sequencing studies of PNKP in patients with MCSZ phenotypes, therefore the clinical sensitivity remains unknown. A study of 500 individuals with various epileptic encephalopathies of unknown caused identified one homozygous pathogenic PNKP variant (Carvill et al. 2013).

Testing Strategy

This test provides full coverage of all coding exons of the PNKP gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

PNKP sequencing is recommended in patients with microcephaly, infantile seizures, and developmental delay with or without progressive neurological symptoms. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PNKP.


Official Gene Symbol OMIM ID
PNKP 605610
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Epileptic Encephalopathy, Early Infantile, 10 AR 613402


  • Carvill GL, Heavin SB, Yendle SC, McMahon JM, O’Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Møller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC. 2013. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genetics 45: 825–830. PubMed ID: 23708187
  • Poulton C, Oegema R, Heijsman D, Hoogeboom J, Schot R, Stroink H, Willemsen MA, Verheijen FW, Spek P van de, Kremer A, Mancini GMS. 2013. Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations. Neurogenetics 14: 43–51. PubMed ID: 23224214
  • Reynolds JJ, Walker AK, Gilmore EC, Walsh CA, Caldecott KW. 2012. Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair. Nucleic Acids Research 40: 6608–6619. PubMed ID: 22508754
  • Shen J, Gilmore EC, Marshall CA, Haddadin M, Reynolds JJ, Eyaid W, Bodell A, Barry B, Gleason D, Allen K, Ganesh VS, Chang BS, et al. 2010. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nature Genetics 42: 245–249. PubMed ID: 20118933


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

loading Loading... ×


An error has occurred while calculating the price. Please try again or contact us for assistance.

View Ordering Instructions

1) Select Test Method (Platform)

1) Select Test Type

2) Select Additional Test Options

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: loading
Patient Prompt Pay Price: loading
A patient prompt pay discount is available if payment is made by the patient and received prior to the time of reporting.
Show Patient Prompt Pay Price
Copy Text to Clipboard