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Ichthyosis Follicularis, Alopecia, and Photophobia (IFAP) Syndrome via the MBTPS2 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
MBTPS2 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9823MBTPS281479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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


  • Renee Bend, PhD

Clinical Features and Genetics

Clinical Features

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD). X-linked Intellectual Disability (XLID) contributes almost 10-15% of intellectual disability (ID) cases in males.

Deficiency of Membrane-Bound Transcription Factor Site-2 Protease (MBTPS2) leads to X-linked Ichthyosis Follicularis, Alopecia, and Photophobia (IFAP) syndrome (with or without BRESHECK syndrome). IFAP syndrome is a multiple congenital malformation disorder and is associated with impaired cholesterol homeostasis and endoplasmic reticulum stress response (Oeffner et al. 2009. PubMed ID: 19361614). Clinical features of IFAP widely vary and may include (but may not be limited to) delayed psychomotor development, motor delay, speech delay, intellectual disability, seizures, brain malformations, microcephaly, short stature, breathing difficulties, inguinal hernia, hearing loss, visceral and skeletal malformations, joint hyper extensibility, dysmorphic facies (eyelid ptosis, cleft palate, large prominent nose, short philtrum, large dysplastic ears), and abnormalities of the skin, nails, hair, chest, ocular, gastrointestinal and genitourinary systems that include ichthyosis follicularis, noncicatricial and nonprogressive alopecia, photophobia and nail dystrophy (Tang et al. 2011. PubMed ID: 21315478, Pietrzak et al. 2012. PubMed ID: 22781927, Izumi et al. 2013. PubMed ID: 23551428, Zhang et al. 2016. PubMed ID: 27663151). Of note, early childhood deaths (within first ~2 years of life) have been reported in severely affected males (Izumi et al. 2013. PubMed ID: 23551428). Carrier females often manifest variable milder abnormalities of the skin, nails and hair, including patchy hair loss, sparse scalp hair, baldness, dry skin, hyperkeratotic plaques, nail dystrophy, linear scalp alopecia, brown scaly plaques, linear atrophy and scaling on the arm, shoulder, waist and legs (Pietrzak et al. 2012. PubMed ID: 22781927).

Interestingly, normal intelligence has also been reported among affected males harboring pathogenic MBTPS2 variants (Oeffner et al. 2009. PubMed ID: 19361614, Aten et al. 2010. PubMed ID: 20672378, Haghighi et al. 2013. PubMed ID: 22931912, Fong et al. 2015. PubMed ID: 25683132, Lindert et al. 2016. PubMed ID: 27380894). Based on a genotype-phenotype correlation study on the pathogenic MBTPS2 variants in male patients with IFAP, pathogenic variants primarily in the transmembrane domains 6–8 were found to be associated with severe phenotypes (Bornholdt et al. 2013. PubMed ID: 23316014). However, since phenotypic heterogeneity has been observed with the same MBTPS2 variant, the role of epigenetic alterations, modifier genes and ethnic background in the phenotypic heterogeneity of IFAP cannot be ruled out (Zhang et al. 2016. PubMed ID: 27663151).


IFAP syndrome is an X-linked disorder, caused by pathogenic variants in MBTPS2. MBTPS2 consists of 11 coding exons and maps to chromosome Xp22.12, encoding a 519 amino acid polypeptide. Membrane-Bound Transcription Factor Site-2 Protease (MBTPS2) is a transmembrane zinc metalloprotease essential for intramembrane proteolysis of sterol-regulatory element-binding proteins (Pietrzak et al. 2012. PubMed ID: 22781927). MBTPS2 functions in the control of cholesterol homeostasis and the ER stress response and has significant implication in development (Zhang et al. 2016. PubMed ID: 27663151). To date, only missense and splice site pathogenic variants have been reported (Human Gene Mutation Database). The disease transmission pattern is primarily X-linked recessive.

Clinical Sensitivity - Sequencing with CNV PGxome

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795). We expect the analytical sensitivity of the MBTPS2 single nucleotide variants to be high.

To date, no gross deletion or duplication involving MBTPS2 has been reported (Human Gene Mutation database).

Testing Strategy

This test provides full coverage of all coding exons of the MBTPS2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Targeted Sanger sequencing in MBTPS2 is appropriate for the family members of patients with MBTPS2 pathogenic variants. Of note, a panel (or exome/genome) sequencing test would nearly always be more appropriate for patients with intellectual disabilities, unless previous clinical knowledge implicates the MBTPS2 gene. Prenatal testing is possible if the genetic diagnosis has been firmly established in an affected family member.


Official Gene Symbol OMIM ID
MBTPS2 300294
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


  • Aten et al. 2010. PubMed ID: 20672378
  • Bornholdt et al. 2013. PubMed ID: 23316014
  • Fong et al. 2015. PubMed ID: 25683132
  • Haghighi et al. 2013. PubMed ID: 22931912
  • Human Gene Mutation Database (Bio-base).
  • Izumi et al. 2013. PubMed ID: 23551428
  • Lindert et al. 2016. PubMed ID: 27380894
  • Oeffner et al. 2009. PubMed ID: 19361614
  • Pietrzak et al. 2012. PubMed ID: 22781927
  • Tang et al. 2011. PubMed ID: 21315478
  • Vissers et al. 2016. PubMed ID: 26503795
  • Zhang et al. 2016. PubMed ID: 27663151


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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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