Restrictive Dermopathy and Mandibuloacral Dysplasia with Type B Lipodystrophy via the ZMPSTE24 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
400 ZMPSTE24$710.00 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 prevalence of these disorders is too low to estimate clinical sensitivity.  Analytical sensitivity should be high as nearly all ZMPSTE24 mutations reported to date are expected to be detected by gene sequencing.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 ZMPSTE24$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features
Restrictive dermopathy (RD; OMIM 275210) is a rare disorder observed in newborns that is characterized by tight, translucent and rigid skin, joint contractures and distinctive craniofacial abnormalities including the hallmark “O” shaped mouth and micrognathia. Newborns with RD rarely live beyond the first week of life. Mandibuloacral dysplasia with type B lipodystrophy (MADB; OMIM 608612) is a progeroid syndrome characterized by mandibular and clavicular hypoplasia, joint contractures, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. In addition to these typical findings, one case of ZMPTE24 associated MADB was found with a complex presentation including congenital myopathy with fiber type disproportion (Ben Yaou et al. Eur J Hum Genet 19:647-654, 2011). This patient was found to be homozygous for a novel ZMPSTE24 missense mutation. A severe presentation of MADB was reported in Japanese siblings who were compound heterozygous for an inactivating nonsense mutation and a missense mutation (Miyoshi et al. Clin Genet 73: 535–544, 2008).
Restrictive dermopathy and mandibuloacral dysplasia may be caused by mutation in the ZMPSTE24 gene or less often by mutations in the LMNA gene. ZMPSTE24 associated RD and MADB are inherited in an autosomal recessive manner (Navarro et al. Hum Molec Genet 14:1503-1513, 2005; Agarwal et al. Hum Molec Genet 12:1995-2001, 2003). LMNA associated RD is inherited in an autosomal dominant manner (Navarro et al. Hum Molec Genet 13:2493-2503, 2004), while LMNA associated mandibuloacral dysplasia with type A lipodystrophy is inherited in an autosomal recessive manner (Novelli et al. Am J Hum Genet 71:426-431, 2002). ZMPSTE24 is located on chromosome 1p34 and encodes a zinc metalloendoproteinase which is involved in processing farnesylated prelamin A to mature lamin A. Consequently, inactivating mutations in the ZMPSTE24 gene lead to loss of expression of lamin A and abnormal patterns of nuclear morphology and mislocalization of lamin-associated proteins (Navarro et al. Hum Molec Genet 13:2493-2503, 2004). The c.1085dupT mutation is the most common ZMPSTE24 mutation associated with RD and is thought to originate from a European founder (Miner Am J Med Genet 152A:2140–2141). Inactivating mutations (nonsense, frame-shift, splice site) are the most common type of mutation in the ZMPSTE24 gene.
Testing Strategy
Testing is accomplished by amplifying each coding exon and ~20 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard dideoxy sequencing methods and a capillary electrophoresis instrument. 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
Clinical presentations consistent with RD or MADB.


Official Gene Symbol OMIM ID
ZMPSTE24 606480
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • Agarwal, A. K., (2003). "Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia." Hum Mol Genet 12(16): 1995-2001. PubMed ID: 12913070
  • Ben Yaou, R., (2011). "Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation." Eur J Hum Genet 19(6): 647-54. PubMed ID: 21267004
  • Miner, J. H. (2010). "Restrictive dermopathy and ZMPSTE24 mutations in Mennonites: Evidence for allelic heterogeneity." Am J Med Genet A 152A(8): 2140-1; author reply 2142. PubMed ID: 20635340
  • Miyoshi, Y., (2008). "Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings." Clin Genet 73(6): 535-44. PubMed ID: 18435794
  • Navarro, C. L., (2004). "Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy." Hum Mol Genet 13(20): 2493-503. PubMed ID: 15317753
  • Navarro, C. L., (2005). "Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors." Hum Mol Genet 14(11): 1503-13. PubMed ID: 15843403
  • Novelli, G., (2002). "Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C." Am J Hum Genet 71(2): 426-31. PubMed ID: 12075506
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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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