Classic lissencephaly via the PAFAH1B1/LIS1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
507 PAFAH1B1$710.00 81406 Add to Order
Targeted Testing

For ordering sequencing of 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
PAFAH1B1 mutations are more common than mutations in the DCX or the TUBA1A genes. Mutations in the PAFAH1B1 gene are estimated to cause approximately 32% of classic lissencephaly cases (Pilz et al. 1998).

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Del/Dup via aCGH

Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
600 PAFAH1B1$990.00 81405 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features
Lissencephaly is defined as "smooth brain" with absent gyri (agyria) or abnormally wide gyri (pachygyria) (Brakovich et al. Ann Neurol 1991; 30:139–46). Classic lissencephaly includes the LIS1-associated, DCX-related, and TUBA1A-related forms as well as the rare Baraitser-Winter syndrome (BWS) (Dobyns et al. Neurology 42:1375-88, 1992; Poirier et al. Hum Mutat 28:1055-64, 2007). LIS1-related lissencephaly, known as Lissencephaly type 1 (LIS1, OMIM# 607432) is caused by cortical malformations due to deficient neuronal migration during embryogenesis. LIS1 consists of variable grades of lissencephaly, ranging from severe complete agyria to mild subcortical band heterotopia (SBH), characterized by subcortical band of symmetric or diffused heterotopic gray matter located beneath the cortex and separated from it by a thin zone of normal white matter. Clinical features of LIS1 include developmental delay, mental retardation and seizures (Dobyns et al. 1992). It has been reported that patients with LIS1-related lissencephaly have 4-layer involvement with more posterior malformation (Forman et al. J Neuropath Exp Neurol 64:847-857, 2005).
LIS1 is inherited as an autosomal dominant disorder. LIS1 is caused by mutations in the PAFAH1B1 (also known as LIS1) gene (Dobyns et al. 1992). PAFAH1B1 gene encodes the LIS1 protein, which interacts with DCX protein. It has been proposed that LIS1and DCX proteins are involved in proper microtubule function in the developing cerebral cortex, which could explain the role of LIS1 in neuronal migration and early embryonic development (Hirotsune et al. Nat Genet 19:333-339, 1998; Caspi et al. Hum Molec Genet 9:2205-2213, 2000). Deletions of 17p13.3 and intragenic deletions and duplications within the PAFAH1B1 gene, as well as a mix of missense, nonsense, splice site and small deletion mutations have been reported. Most of the reported PAFAH1B1 whole gene and intragenic deletion and duplication mutations occurred de novo (Pilz et al. Hum Mol Genet 7:2029-37, 1998; Cardoso et al. Hum Mol Genet 9:3019-28, 2000; Uyanik et al. Neurology 69:442-447, 2007).
Testing Strategy
This test involves bidirectional sequencing using genomic DNA of the 10 coding exon (exons 2-11) of the PAFAH1B1 gene. The full coding region of each exon plus ~10 bp of flanking non-coding DNA on each side are sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
Candidates for this test are patients with symptoms consistent with classical lissencephaly 1 and family members of patients who have known PAFAH1B1 mutations. Conclusive connections between clinical features and PAFH1B1 or TUBA1A mutations have not been made.


Official Gene Symbol OMIM ID
PAFAH1B1 601545
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Lissencephaly 1 607432


Genetic Counselors
  • Barkovich, A. J., (1991). "The spectrum of lissencephaly: report of ten patients analyzed by magnetic resonance imaging." Ann Neurol 30(2): 139-46. PubMed ID: 1897907
  • Cardoso, C., (2000). "The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene." Hum Mol Genet 9(20): 3019-28. PubMed ID: 11115846
  • Caspi, M., (2000). "Interaction between LIS1 and doublecortin, two lissencephaly gene products." Hum Mol Genet 9(15): 2205-13. PubMed ID: 11001923
  • Dobyns, W. B., (1992). "Causal heterogeneity in isolated lissencephaly." Neurology 42(7): 1375-88. PubMed ID: 1620349
  • Forman, M. S., (2005). "Genotypically defined lissencephalies show distinct pathologies." J Neuropathol Exp Neurol 64(10): 847-57. PubMed ID: 16215456
  • Hirotsune, S., (1998). "Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality." Nat Genet 19(4): 333-9. PubMed ID: 9697693
  • Pilz, D. T., (1998). "LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation." Hum Mol Genet 7(13): 2029-37. PubMed ID: 9817918
  • Poirier, K., (2007). "Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A)." Hum Mutat 28(11): 1055-64. PubMed ID: 17584854
  • Uyanik, G., (2007). "Location and type of mutation in the LIS1 gene do not predict phenotypic severity." Neurology 69(5): 442-7. PubMed ID: 17664403
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  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 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 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 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

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 10 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.

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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.
  • 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.


(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.


(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.


(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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