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Amelogenesis Imperfecta via the AMELX Gene

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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
AMELX 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9161AMELX81479 81479,81479 $990 Order Options and Pricing

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Stela Berisha, PhD, FACMG

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. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Stela Berisha, PhD, FACMG

Clinical Features and Genetics

Indications for Test

Candidates for this test are patients with symptoms consistent with X-linked hypoplastic/hypomaturation amelogenesis imperfecta and the family members of patients who have known AMELX mutations.

Clinical Features

Amelogenesis imperfecta (AI) is a heterogeneous condition of enamel defects affecting both primary and permanent dentitions. Affected teeth are usually small, discolored, pitted or grooved, and prone to rapid wear and breakage. Based on clinical and radiographic features of the enamel defects as well as on the mode of inheritance pattern, AI has been divided into 14 different subtypes, which can be grouped into four major forms: hypoplastic, hypomaturation, hypocalcified, and hypomaturation-hypoplastic with taurodontism (Witkop et al. 1988). Hypoplastic AI shows reduced enamel volume with pits or grooves, but enamel is usually hard and translucent. Hypomaturation and hypocalcified AI have hypomineralized enamel with nearly normal matrix volume. Hypocalcified AI may present soft enamel which can be easily scraped away by attrition. Hypomaturation enamel is hard, but brittle and prone to breaking off. Hypomaturation-hypoplastic with taurodontism shows reduced, hypomineralized enamel with pits; in addition, molars or other teeth may present enlarged pulp chambers (Witkop et al. 1988; Crawford et al. 2007).

AI and AI-related syndromes are currently known to be caused by mutations in the following genes: AMELX (Aldred et al. 1992), DLX3 (Price et al. 1998), ENAM (Mardh et al. 2002), KLK4 (Hart et al. 2004), MMP20 (Kim et al. 2005), FAM83H (Lee et al. 2008; Kim et al. 2008), WDR72 (El-Sayed et al. 2009), FAM20A (O'Sullivan et al. 2011), C4orf26 (Parry et al. 2012), ROGDI (Schossig et al. 2012), SLC24A4 (Parry et al. 2013), ITGB6 (Poulter et al. 2013; Wang et al. 2013), LAMB3 (Kim et al. 2013), CNNM4 (Parry et al. 2009) and NHS (Burdon et al. 2003).

Enamel defects can also occur as syndrome disorders. For example, Kohlschütter–Tönz syndrome features enamel defects, psychomotor delay or regression and seizures caused by ROGDI mutations (Tucci et al. 2013); Nance-Horan syndrome (NHS) is characterized by congenital cataracts, dental anomalies, dysmorphic features and mental retardation caused by mutations in the NHS gene (Burdon et al. 2003); Jalili Syndrome features autosomal-Recessive Cone-Rod dystrophy and amelogenesis Imperfecta caused by mutations in the CNNM4 gene (Parry et al. 2009); and mutations in the FAM20A gene cause amelogenesis imperfecta and gingival hyperplasia syndrome as well as amelogenesis imperfecta and renal syndrome (O’Sullivan et al. 2011; Wang et al. 2013).

Genetics

Mutations in the AMELX gene cause X-linked hypoplastic and /or hypomaturation amelogenesis imperfecta. Males are predominantly affected, but heterozygous female carriers may develop enamel defects. Clinical manifestations in females appear to be largely determined by random X-inactivation. The amelogenin coded by the AMELX gene is the major protein of enamel organic matrix and plays a key role in enamel structure and mineralization. To date, more than 20 unique pathogenic variants have been documented. They are missense (6/22), nonsense (2/22), small deletions (8/22), and large deletions involving the AMELX gene (6/22) (Chan et al., 2011; Wright et al. 2011; Hu et al. 2012; Human Gene Mutation Database). A large heterozygous deletion involving AMELX was reported in a female patient affected with microphthalmia with linear skin defects and amelogenesis imperfecta (Hobson et al. 2009).

Clinical Sensitivity - Sequencing with CNV PGxome

In one study, AMELX mutations were identified in 2 out of 39 clinical diagnosed AI families. Both families demonstrated X-linked inheritance (Chan et al. 2011). In another study, AMELX mutations were reported to account for ~23% of pathogenic mutations found in patients affected with AI among the six genes tested (AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72) (Wright et al. 2011).

Six gross deletions/duplications have been reported in AMELX (Hobson et al. 2009; HU et al. 2012; Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the AMELX 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

Candidates for this test are patients with symptoms consistent with X-linked hypoplastic/hypomaturation amelogenesis imperfecta and the family members of patients who have known AMELX mutations.

Gene

Official Gene Symbol OMIM ID
AMELX 300391
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Amelogenesis Imperfecta, Type Ie 301200

Related Tests

Name
Amelogenesis Imperfecta via the DLX3 Gene
Amelogenesis Imperfecta via the ENAM Gene
Amelogenesis Imperfecta via the FAM83H Gene
Amelogenesis Imperfecta via the KLK4 Gene
Amelogenesis Imperfecta via the MMP20 Gene
Amelogenesis Imperfecta via the ODAPH (C4orf26) Gene
Amelogenesis Imperfecta via the WDR72 Gene
Epidermolysis Bullosa with Pyloric Atresia via the ITGA6 Gene
Kohlschutter-Tonz syndrome (KTS) via the ROGDI Gene

Citations

  • Aldred MJ, Crawford PJ, Roberts E, Thomas NS. 1992. Identification of a nonsense mutation in the amelogenin gene (AMELX) in a family with X-linked amelogenesis imperfecta (AIH1). Hum. Genet. 90: 413–416. PubMed ID: 1483698
  • Burdon KP, McKay JD, Sale MM, Russell-Eggitt IM, Mackey DA, Wirth MG, Elder JE, Nicoll A, Clarke MP, FitzGerald LM, Stankovich JM, Shaw MA, et al. 2003. Mutations in a Novel Gene, NHS, Cause the Pleiotropic Effects of Nance-Horan Syndrome, Including Severe Congenital Cataract, Dental Anomalies, and Mental Retardation. Am J Hum Genet 73: 1120–1130. PubMed ID: 14564667
  • Chan H-C, Estrella NMRP, Milkovich RN, Kim J-W, Simmer JP, Hu JC-C. 2011. Target gene analyses of 39 amelogenesis imperfecta kindreds: AI mutations. European Journal of Oral Sciences 119: 311–323. PubMed ID: 22243262
  • Chan H-C, Estrella NMRP, Milkovich RN, Kim J-W, Simmer JP, Hu JC-C. 2011. Target gene analyses of 39 amelogenesis imperfecta kindreds: AI mutations. European Journal of Oral Sciences 119: 311–323. PubMed ID: 22243262
  • Crawford PJ, Aldred M, Bloch-Zupan A. 2007. Amelogenesis imperfecta. Orphanet Journal of Rare Diseases 2: 17. PubMed ID: 17408482
  • El-Sayed W, Parry DA, Shore RC, Ahmed M, Jafri H, Rashid Y, Al-Bahlani S, Harasi S Al, Kirkham J, Inglehearn CF, Mighell AJ. 2009. Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta. The American Journal of Human Genetics 85: 699–705. PubMed ID: 19853237
  • Hart PS. 2004. Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta. Journal of Medical Genetics 41: 545–549. PubMed ID: 15235027
  • Hobson GM, Gibson CW, Aragon M, Yuan Z, Davis-Williams A, Banser L, Kirkham J, Brook AH. 2009. A Large X-Chromosomal Deletion is Associated with Microphthalmia with Linear Skin Defects (MLS) and Amelogenesis Imperfecta (XAI). Am J Med Genet A 149A: 1698–1705. PubMed ID: 19610109
  • Hobson GM, Gibson CW, Aragon M, Yuan Z, Davis-Williams A, Banser L, Kirkham J, Brook AH. 2009. A large X-chromosomal deletion is associated with microphthalmia with linear skin defects (MLS) and amelogenesis imperfecta (XAI). American Journal of Medical Genetics Part A 149A: 1698–1705. PubMed ID: 19610109
  • Hu JC-C, Chan H-C, Simmer SG, Seymen F, Richardson AS, Hu Y, Milkovich RN, Estrella NMRP, Yildirim M, Bayram M, Chen C-F, Simmer JP. 2012. Amelogenesis Imperfecta in Two Families with Defined AMELX Deletions in ARHGAP6. PLoS ONE 7: e52052. PubMed ID: 23251683
  • Hu JC-C, Chan H-C, Simmer SG, Seymen F, Richardson AS, Hu Y, Milkovich RN, Estrella NMRP, Yildirim M, Bayram M, Chen C-F, Simmer JP. 2012. Amelogenesis Imperfecta in Two Families with Defined AMELX Deletions in ARHGAP6. PLoS ONE 7: e52052. PubMed ID: 23251683
  • Human Gene Mutation Database (Bio-base).
  • Human Gene Mutation Database (Bio-base).
  • Kim J, Simmer J, Hart T, Hart P, Ramaswami M, Bartlett J, Hu J. 2005. MMP-20 mutation in autosomal recessive pigmented hypomaturation amelogenesis imperfecta. J Med Genet 42: 271–275. PubMed ID: 15744043
  • Kim J-W, Lee S-K, Lee ZH, Park J-C, Lee K-E, Lee M-H, Park J-T, Seo B-M, Hu JC-C, Simmer JP. 2008. FAM83H Mutations in Families with Autosomal-Dominant Hypocalcified Amelogenesis Imperfecta. The American Journal of Human Genetics 82: 489–494. PubMed ID: 18252228
  • Kim JW, Seymen F, Lee KE, Ko J, Yildirim M, Tuna EB, Gencay K, Shin TJ, Kyun HK, Simmer JP, Hu JC-C. 2013. LAMB3 mutations causing autosomal-dominant amelogenesis imperfecta. J. Dent. Res. 92: 899–904. PubMed ID: 23958762
  • Lee S-K, Hu JC-C, Bartlett JD, Lee K-E, Lin BP-J, Simmer JP, Kim J-W. 2008. Mutational Spectrum of FAM83H: The C-Terminal Portion is Required for Tooth Enamel Calcification. Hum Mutat 29: E95–E99. PubMed ID: 18484629
  • Mårdh CK, Bäckman B, Holmgren G, Hu JC-C, Simmer JP, Forsman-Semb K. 2002. A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2). Hum. Mol. Genet. 11: 1069–1074. PubMed ID: 11978766
  • O’Sullivan J, Bitu CC, Daly SB, Urquhart JE, Barron MJ, Bhaskar SS, Martelli-Junior H, Santos Neto PE dos, Mansilla MA, Murray JC, Coletta RD, Black GCM, et al. 2011. Whole-Exome Sequencing Identifies FAM20A Mutations as a Cause of Amelogenesis Imperfecta and Gingival Hyperplasia Syndrome. Am J Hum Genet 88: 616–620. PubMed ID: 21549343
  • Parry DA, Brookes SJ, Logan CV, Poulter JA, El-Sayed W, Al-Bahlani S, Harasi S Al, Sayed J, Raïf EM, Shore RC, Dashash M, Barron M, et al. 2012. Mutations in C4orf26, Encoding a Peptide with In Vitro Hydroxyapatite Crystal Nucleation and Growth Activity, Cause Amelogenesis Imperfecta. The American Journal of Human Genetics 91: 565–571. PubMed ID: 22901946
  • Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, Bloch-Zupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, et al. 2009. Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta. Am J Hum Genet 84: 266–273. PubMed ID: 19200525
  • Parry DA, Poulter JA, Logan CV, Brookes SJ, Jafri H, Ferguson CH, Anwari BM, Rashid Y, Zhao H, Johnson CA, Inglehearn CF, Mighell AJ. 2013. Identification of Mutations in SLC24A4, Encoding a Potassium-Dependent Sodium/Calcium Exchanger, as a Cause of Amelogenesis Imperfecta. The American Journal of Human Genetics 92: 307–312. PubMed ID: 23375655
  • Poulter JA, Brookes SJ, Shore RC, Smith CEL, Farraj L Abi, Kirkham J, Inglehearn CF, Mighell AJ. 2013. A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta. Human Molecular Genetics. PubMed ID: 24319098
  • Price JA, Wright JT, Kula K, Bowden DW, Hart TC. 1998. A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families. J Med Genet 35: 825–828. PubMed ID: 9783705
  • Schossig A, Wolf NI, Fischer C, Fischer M, Stocker G, Pabinger S, Dander A, Steiner B, Tonz O, Kotzot D, Haberlandt E, Amberger A, et al. 2012. Mutations in ROGDI Cause Kohlschütter-Tönz Syndrome. Am J Hum Genet 90: 701–707. PubMed ID: 22424600
  • Tucci A, Kara E, Schossig A, Wolf NI, Plagnol V, Fawcett K, Paisán-Ruiz C, Moore M, Hernandez D, Musumeci S. 2013. Kohlschütter–Tönz Syndrome: Mutations in ROGDI and Evidence of Genetic Heterogeneity. Human mutation 34: 296–300. PubMed ID: 23086778
  • Wang S-K, Choi M, Richardson AS, Reid BM, Lin BP, Wang SJ, Kim J-W, Simmer JP, Hu JC-C. 2013. ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta. Hum. Mol. Genet. ddt611. PubMed ID: 24305999
  • Witkop CJ. 1988. Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classification. Journal of Oral Pathology & Medicine 17: 547–553. PubMed ID: 3150442
  • Wright JT, Torain M, Long K, Seow K, Crawford P, Aldred MJ, Hart PS, Hart TC. 2011. Amelogenesis Imperfecta: Genotype-Phenotype Studies in 71 Families. Cells Tissues Organs 194: 279–283. PubMed ID: 21597265
  • Wright JT, Torain M, Long K, Seow K, Crawford P, Aldred MJ, Hart PS, Hart TC. 2011. Amelogenesis Imperfecta: Genotype-Phenotype Studies in 71 Families. Cells Tissues Organs 194: 279–283. PubMed ID: 21597265

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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.
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  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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  • 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.

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PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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