FTO-Deficiency Syndrome via the FTO 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
5634 FTO$910.00 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

Genetic variants have been found responsible in 25-50% of ID cases and this percentage increases proportionally with the severity of the phenotype (McLaren and Bryson 1987). To date, a total of 10 homozygous individuals from two families have been reported with missense variants in their FTO gene all presenting with similar clinical features.

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Clinical Features

Intellectual disability (ID) refers to significant impairment of cognitive and adaptive development (intelligence quotient, IQ<70) due to abnormalities of brain structure and/or function (American Association of Intellectual and Developmental Disabilities, AAIDD). ID is not a single entity, but rather a general symptom of neurologic dysfunction that is diagnosed before age 18 in ~1-3% of the population, irrespective of any social class and culture (Kaufman et al. 2010; Vissers et al. 2016). ID and Autism Spectrum Disorders (ASD) are also highly comorbid with each other, suggesting shared etiologies.

FTO-Deficiency Syndrome (also known as Growth Retardation, Developmental Delay, and Facial Dysmorphism) is a rare syndromic from of ID characterized by developmental delay and distinctive dysmorphic features. Other clinical features include: microcephaly, failure to thrive, decreased brain volume, left ventricular hypertrophy, bilateral hearing loss, and in some cases genital anomalies and cleft palate (Daoud et al. 2016; Boissel et al. 2009). Homozygous missense variants within the FTO gene have been identified to segregate with the clinical features of FTO-Deficiency Syndrome in 10 affected individuals from two families.


Intellectual disability is inherited in a multifactorial fashion, with heritability estimates ranging between 15-50% (Larsen et al. 2016; Karam et al. 2015). Approximately 30% more males than females are diagnosed with ID, yet the male-to-female ratio decreases with decreasing IQ (American Psychiatric Association 2000). Co-occurring ASD and ID has a similar male-to-female prevalence ratio of ~4:1 (Christensen et al. 2016). Single nucleotide polymorphisms within the first intron of FTO have also been associated with childhood and adult obesity in multiple human populations and in mouse models (Fawcett et al. 2010; Church et al. 2010).

FTO-Deficiency Syndrome has been reported in individuals with homozygous missense variants in the 2-oxogluterate binding domain of FTO, supporting an autosomal recessive mode of inheritance.

The human FTO gene contains 9 protein-coding exons which encode a 505 amino acid protein. Bacterial and human homologs of FTO are involved in the repair of alkylated DNA and RNA damage from oxidative demethylation. FTO has also been shown to demethylate m6A in mRNA, which plays an important role in gene expression, mRNA processing, and transcript localization (Dominissini et al. 2012). In vitro studies of recombinant human FTO protein with and without a reported missense variant reveal a significant impact on the demethylase activity of the protein (Boissel et al. 2009) The FTO gene (fat mass and obesity-associated) encodes a nuclear iron-dependent oxygenase that is part of the AlkB homologue subfamily (Daoud et al. 2016; Boissel et al. 2009). The FTO protein is hypothesized to be critical for normal development of the nervous and cardiovascular systems through gene regulation (Daoud et al. 2016). The FTO gene is apparently ubiquitously expressed, with highest levels of expression observed in the human central nervous system, liver, and various structures of the heart (Boissel et al. 2009).

Testing Strategy

This test involves bidirectional sequencing using genomic DNA of all coding exons of the FTO gene plus ~10 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known pathogenic variants or to confirm research results. To date, both missense variants reported in individuals with FTO-Deficiency Syndrome have been reported within exon 5 of the FTO gene (Daoud et al. 2016).

Indications for Test

Individuals with family members known to be carriers of pathogenic variants within the FTO gene and/or presenting with severe growth delay and the distinctive features described are good candidates for this test. Of note, missense variants resulting in FTO-Deficiency Syndrome have been reported in families of Arab, Palestinian, or Tunisian decent (Daoud et al. 2016; Boissel et al. 2009).


Official Gene Symbol OMIM ID
FTO 610966
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection


Genetic Counselors
  • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 2000. Text Revision. 4.
  • Boissel S. et al. 2009. American Journal of Human Genetics. 85: 106-11. PubMed ID: 19559399
  • Christensen D.L. et al. 2016. Morbidity and Mortality Weekly Report. 65: 1-23. PubMed ID: 27031587
  • Church C. et al. 2010. Nature Genetics. 42: 1086-92. PubMed ID: 21076408
  • Daoud H. et al. 2016. Journal of Medical Genetics. 53: 200-7. PubMed ID: 26378117
  • Dominissini D. et al. 2012. Nature. 485: 201-6. PubMed ID: 22575960
  • Fawcett K.A., Barroso I. 2010. Trends in Genetics. 26: 266-74. PubMed ID: 20381893
  • Karam S.M. et al. 2015. American Journal of Medical Genetics. Part A. 167: 1204-14. PubMed ID: 25728503
  • Kaufman L. et al. 2010. Journal of Neurodevelopmental Disorders. 2: 182-209. PubMed ID: 21124998
  • Larsen E. et al. 2016. Molecular Autism. 7: 44. PubMed ID: 27790361
  • McLaren J., Bryson S.E. 1987. American Journal of Mental Retardation. 92: 243-54. PubMed ID: 3322329
  • Vissers L.E. et al. 2016. Nature Reviews. Genetics. 17: 9-18. PubMed ID: 26503795
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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.

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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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