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Hereditary Fructose Intolerance via the ALDOB 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
9519 ALDOB 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9519ALDOB81479 81479,81479 $890 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 backbone).

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

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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

Hereditary fructose intolerance (HFI) is a congenital condition that is characterized by abdominal pain, vomiting and hypoglycemia shortly after the ingestion of fructose, sucrose, or sorbitol. Effects during infancy can be severe and become apparent either upon the initiation of weaning from breastfeeding or upon the ingestion of fructose-containing infant formula. Feeding difficulties and overall failure to thrive also often accompany the primary symptoms in infants. In undiagnosed individuals, continued ingestion of the toxic sugars can lead to further growth retardation, hepatic and renal injury, and can eventually lead to liver and kidney failure, coma and death, especially in small infants. Surviving infants and children typically develop strong aversions to foods that induce symptoms and have far lower rates of dental caries than the general population as a result of their decreased sugar consumption. However, even this strong food aversion is not typically sufficient to eliminate all foods containing noxious sugars from the diet, and thus affected individuals may suffer from episodic symptoms throughout life, although the effects generally become less severe with age. In some patients, hepatomegaly and elevated liver transaminases occur when fructose sources are not completely eliminated from the diet. If an individual remains undiagnosed, IV-infusions containing fructose, sucrose or sorbitol may cause life-threatening complications (Ali et al. 1998; Cos 1994; Steinmann et al. 2014).

Dietary exclusion of fructose, sucrose and sorbitol (including that found in medicines) results in the elimination of symptoms and complete recovery, if diagnosis is made early enough. Individuals who completely eliminate the noxious sugars from their diet are anticipated to have a normal life expectancy (Ali et al. 1998; Cos 1994; Steinmann et al. 2014).

Genetics

Hereditary fructose intolerance is an autosomal recessive disorder, and ALDOB is the only gene in which defects are known to cause HFI. To date, approximately 60 causative variants have been reported in the ALDOB gene (Steinmann et al. 2014; Human Gene Mutation Database; HFI Mutational Database). About one-third of reported pathogenic variants are missense, with the remainder being nonsense, splicing and small insertions and deletions. Two variants upstream of the coding sequence, c.-214G>A and c.-11+1G>C, have also been reported (Coffee and Tolan 2010). The variants are spread throughout the ALDOB gene, with no known mutational hotspots (HFI Mutational Database). Three variants (A150P, A175D and N335K) are known to be the most common pathogenic variants and, in fact, have been shown to account for upwards of 60% of HFI cases in European and North American individuals (Cross et al. 1990; Davit-Spraul et al. 2008; Santer et al. 2005). Most other variants are rare or private mutations. A relatively small percentage of cases (~3-5%) have been attributed to larger exonic deletions that are generally undetectable via standard Sanger sequencing (Human Gene Mutation Database; Cross and Cox 1990; Ferri et al. 2012).

Hereditary Fructose Intolerance is caused by catalytic defects in the aldolase B protein, also known as fructose-1,6-bisphosphate aldolase B. Two other isozymes, aldolase A and aldolase C, are found in humans. The tissues in which these isozymes predominate differ from aldolase B, which is expressed mainly in the liver, kidneys and small intestine. Aldolase B catalyzes the conversion of fructose-1-phosphate to D-glyceraldehyde and dihydroxyacetone phosphate, as well as the conversion of fructose-1,6-bisphosphate to D-glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. It is thought that the clinical symptoms observed in aldolase B deficient individuals are due to both the buildup of the fructose-1-phosphate and fructose-1,6-bisphosphate precursors, as well as due to the decreased amount of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate available to continue through the glycolytic pathway (Ali et al. 1998; Cos 1994; Steinmann et al. 2014).

Clinical Sensitivity - Sequencing with CNV PGxome

Overall, the analytical sensitivity of this test is expected to be high because the great majority of variants reported to date in the ALDOB gene are detectable via DNA sequencing. Santer and colleagues (2005) reported two causative variants in 93% of the 72 HFI patients they studied, and one causative variant in the remaining 7%, for an overall detection rate of ~96.5% (139 out of 144 alleles carried causative variants). Their cohort of patients consisted primarily of individuals of German and Mediterranean heritage. In 2008, Davit-Spraul and colleagues reported the identification of two causative variants in 96.5% of individuals in a group of 92 HFI patients. A single causative variant was identified in the remaining 3.5% of patients, for an overall detection rate of ~98.4% (181 out of 184 alleles carried causative variants). Approximately three-fourths of the patients in their cohort were French, with the remaining being of Belgian or Mediterranean heritage.

A small number of patients have been shown to carry large, exonic deletions that are undetectable via sequencing, which may account for the remaining unidentified causative variants in these studies.

Testing Strategy

This test provides full coverage of all coding exons of the ALDOB 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).

Additionally, ALDOB gene sequencing includes the regions encompassing the documented variants c.-214G>A and c.-11+1G>C.

Indications for Test

Individuals with a positive intravenous fructose load test or aldolase B enzymatic assay results from liver or intestinal biopsy samples are good candidates for this test, as are those exhibiting clinical symptoms suggestive of hereditary fructose intolerance. Family members of patients who have known ALDOB variants are candidates. We will also sequence the ALDOB gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
ALDOB 612724
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Hereditary Fructose Intolerance AR 229600

Citations

  • Ali M, Rellos P, Cox TM. 1998. Hereditary fructose intolerance. J. Med. Genet. 35: 353–365.  PubMed ID: 9610797
  • Coffee EM, Tolan DR. 2010. Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance. J. Inherit. Metab. Dis. 33: 715–725. PubMed ID: 20882353
  • Cox TM. 1994. Aldolase B and fructose intolerance. FASEB J 8: 62–71. PubMed ID: 8299892
  • Cross NC, Cox TM. 1990. Partial aldolase B gene deletions in hereditary fructose intolerance. Am J Hum Genet 47: 101–106.  PubMed ID: 2349937
  • Cross NC, Franchis R de, Sebastio G, Dazzo C, Tolan DR, Gregori C, Odievre M, Vidailhet M, Romano V, Mascali G. 1990. Molecular analysis of aldolase B genes in hereditary fructose intolerance. Lancet 335: 306–309. PubMed ID: 1967768
  • Davit-Spraul A, Costa C, Zater M, Habes D, Berthelot J, Broué P, Feillet F, Bernard O, Labrune P, Baussan C. 2008. Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France--identification of eight new mutations. Mol. Genet. Metab. 94: 443–447. PubMed ID: 18541450
  • Ferri L, Caciotti A, Cavicchi C, Rigoldi M, Parini R, Caserta M, Chibbaro G, Gasperini S, Procopio E, Donati MA, Guerrini R, Morrone A. 2012. Integration of PCR-Sequencing Analysis with Multiplex Ligation-Dependent Probe Amplification for Diagnosis of Hereditary Fructose Intolerance. JIMD Rep 6: 31–37. PubMed ID: 23430936
  • HFI Mutational Database.
  • Santer R, Rischewski J, Weihe M von, Niederhaus M, Schneppenheim S, Baerlocher K, Kohlschütter A, Muntau A, Posselt H-G, Steinmann B, Schneppenheim R. 2005. The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. Hum. Mutat. 25: 594. PubMed ID: 15880727

Ordering/Specimens

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


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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