Pelger-Huet Anomaly and Greenberg Skeletal Dysplasia via the LBR Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1033 LBR$870.00 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

The incidence of PHA is around 0.01-0.1% worldwide, but is higher in areas of northern Sweden and southeastern Germany (Hoffman et al. 2002); the frequency of Greenberg skeletal dysplasia is unclear. Only a small number of PHA and Greenberg skeletal dysplasia cases have been reported in the literature so the rate of mutation detection among patients remains unclear.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 LBR$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

To date, no large genomic deletions or duplications in the LBR gene have been reported in PHA or Greenberg skeletal dysplasia patients.

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Clinical Features

Pelger-Huet Anomaly (PHA) was first reported in the late 1920s and early 1930s and is characterized by hyposegmentation of nuclei and abnormal chromatin organization in blood granulocytes (Pelger, K Ned T Geneesk 72:1178, 1928; Huet, G.H. Maandschr. Kindergeneesk 1:173, 1932). Data suggest PHA is a due to a deficiency of the lamin B receptor protein within the nuclear membrane (Hoffman et al. 2002). The abnormal neutrophils found in PHA patients are reported to function properly (Johnson et al. 1980), but severe (homozygous) forms of the disease may be accompanied by mental retardation and skeletal anomalies including disproportionate body stature, macrocephaly, ventricular septal defect, and short fingers (Hoffman et al. 2002). A related disorder, Hydrops-ectopic calcification-"moth-eaten" (HEM) or Greenberg skeletal dysplasia is characterized by a phenotype similar to that found in severe forms of PHA and may also present with fetal hydrops and abnormal chondro-osseous calcification often resulting in prenatal death (Waterham et al. 2003; Clayton et al. 2010). Since healthy relatives of patients with Greenberg skeletal dysplasia were found to have abnormal granulocyte neuclei, it is suspected that classic PHA and Greenberg skeletal dysplasia represent the heterozygous and homozygous states of lamin B receptor deficiency, respectively (Waterham et al. 2003).


Mutations in the LBR gene are involved with autosomal dominant Pelger-Huet Anomaly (PHA) (Hoffman et al. 2002) and autosomal recessive Greenberg skeletal dysplasia (Waterham et al. 2003). The LBR gene encodes the lamin B receptor which comprises an N-terminal lamin B / DNA-binding domain and a C-terminal sterol reductase-like domain (Holmer et al. 1998). The lamin B receptor is highly conserved evolutionarily and helps maintain the structural integrity of the inner-nuclear membrane through binding to chromatin and nuclear lamins (Burke and Ellenberg 2002). Decreased sterol reductase function of the lamin B receptor is found in Greenberg skeletal dystrophy patients (Waterham et al. 2003) thereby identifying Greenberg skeletal dysplasia as a disorder of cholesterol biosynthesis. The frequency of PHA is around 0.01-0.1% worldwide, but is higher in areas of northern Sweden and southeastern Germany (Hoffman et al. 2002); the frequency of Greenberg skeletal dysplasia is unclear. Causative variants are spread throughout the 13 coding exons of the LBR gene and include roughly equal proportions of missense / nonsense mutations and small deletions or insertions.

Testing Strategy

Our DNA test involves bidirectional Sanger sequencing of all 13 coding exons (exons 2-14) of the LBR gene plus ~ 20 bp of flanking non-coding DNA on either side of each exon. 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

All patients with clinical and biochemical features of PHA or Greenberg skeletal dysplasia and relatives of these patients.


Official Gene Symbol OMIM ID
LBR 600024
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Greenberg Dysplasia 215140
Pelger-Huet Anomaly 169400


Genetic Counselors
  • Burke B, Ellenberg J. 2002. Remodelling the walls of the nucleus. Nat. Rev. Mol. Cell Biol. 3: 487–497. PubMed ID: 12094215
  • Clayton P, Fischer B, Mann A, Mansour S, Rossier E, Veen M, Lang C, Baasanjav S, Kieslich M, Brossuleit K. 2010. Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein. Nucleus 1: 354. PubMed ID: 21327084
  • Hoffmann K, Dreger CK, Olins AL, Olins DE, Shultz LD, Lucke B, Karl H, Kaps R, Müller D, Vayá A, Aznar J, Ware RE, et al. 2002. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huët anomaly). Nature Genetics 31:410-414. PubMed ID: 12118250
  • Holmer L, Pezhman A, Worman HJ. 1998. The human lamin B receptor/sterol reductase multigene family. Genomics 54: 469–476. PubMed ID: 9878250
  • Johnson CA, Bass DA, Trillo AA, Snyder MS, DeChatelet LR. 1980. Functional and metabolic studies of polymorphonuclear leukocytes in the congenital Pelger-Huet anomaly. Blood 55: 466–469. PubMed ID: 6244014
  • Waterham HR, Koster J, Mooyer P, Noort G van, Kelley RI, Wilcox WR, Wanders RJA, Hennekam RCM, Oosterwijk JC. 2003. Autosomal Recessive HEM/Greenberg Skeletal Dysplasia Is Caused by 3 beta-hydroxysterol delta 14-reductase Deficiency Due to Mutations in the Lamin B Receptor Gene. Am J Hum Genet 72: 1013–1017. PubMed ID: 12618959
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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 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.

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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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