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Autism Spectrum Disorders via the KMT5B (SUV420H1) Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
3770 KMT5B$970.00 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

Currently, the contribution of de novo and inherited factors to Autism Spectrum Disorder (ASD) risk is estimated to be approximately 50%-60% (Krumm et al. 2015). KMT5B is categorized as a ‘high confidence’ gene candidate for ASD in the Simons Foundation Autism Research Initiative (SFARI) Database (https://gene.sfari.org/GeneDetail/KMT5B). However, more than 700 genes have been associated with ASD features (Bourgeron 2016). Based on multiple recent large sequencing studies, causative variants in KMT5B were collectively identified in approximately 0.07% of ASD probands (14/19,778) (Iossifov et al. 2014; DeRubies et al. 2014; Stessman et al. 2017).

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Clinical Features

Autism Spectrum Disorders (ASD) include several neurodevelopmental disorders characterized by varying degrees of social impairment, communication ability, and propensity for restricted interests and repetitive behavior(s) (Levy et al. 2009). ASD usually presents by age 3. Diagnosis is based on the degree and severity of symptoms and behaviors (Diagnostic and Statistical Manual of Mental Disorders (DSM-5); McPartland et al. 2016). Comorbidities occur in more than 70% of cases and include intellectual disability (ID), epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi 2016). Recent studies using whole exome trio studies have identified novel gene candidates, with familial and de novo variants from several hundred genes now implicated in the development of ASD (Bourgeron 2016).

Genetics

Genetic aberrations are reported to be responsible for 50%-90% and 15%-50% of ASD and ID cases, respectively, and inheritance overall is multifactorial (Larsen et al. 2016; Karam et al. 2015). Incidence of ASD is approximately 1 in 68 individuals with a male-to-female ratio of 4:1 (Center for Disease Control 2014). De novo missense and likely gene disrupting variants are 15% and 75% more frequent in ASD patients than unaffected controls, respectively (Iossifov et al. 2014). Several studies have identified de novo missense, nonsense, and frameshift variants in KMT5B within individuals presenting with a neurodevelopmental disorder (Iossifov et al. 2012; Sanders et al. 2012; De Rubeis et al. 2014; Stessman et al. 2017). Based on the large number of reported heterozygous de novo variants in affected individuals, it appears KMT5B pathogenic variants lead to ASD/ID symptoms in an autosomal dominant manner. However, the precise molecular mechanism is unclear (Stessman et al. 2017).

KMT5B (lysine (K)-specific methyltransferase 5B) (also known as SUV420H1, suppressor of variegation 4-20 homolog 1) is a histone lysine N-methyltransferase involved in chromatin modifications and gene regulation. The role of KMT5B in brain development is unclear; however histone H4 K20 trimethylation via KMT5B has been shown to regulate the cell cycle of baboon neural stem progenitor cells (Rhodes et al. 2016).  RNAi knockdown studies of the Drosophila KMT5B homolog also suggest an impact on habitual learning (Stessman et al. 2017). Individuals with likely gene disrupting variants in KMT5B present with intellectual disability/developmental delay (100% of cases to date), ASD (83%), language delay (75%), motor delay (60%), febrile seizures (60%), and in some cases attention deficits (Stessman et al. 2017).

In human cells, the KMT5B (SUV420H1) gene encodes two alternatively splice isoforms, the longest including 10 exons that encode an 885 amino acid protein. Both isoforms contain a SET domain (residues 191-303). This domain is present in all known human histone methyltransferases and hypothesized to mediate interactions with dual-specificity phosphatase-like proteins (Lachner and Jenuwein 2002; Wu et al. 2013). At least 4 de novo variants have been reported within the SET domain, however, likely gene disrupting variants upstream and downstream of the SET domain have been reported (Stessman et al. 2017).

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons (longest isoform) of the KMT5B gene plus ~20 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.

Indications for Test

To our knowledge, nearly all reported pathogenic variants in KMT5B have been de novo in nature. However, individuals with family members having known KMT5B variants and/or displaying ASD, intellectual disability, or developmental delay features (also language and motor delay, febrile seizures, and attention deficits) are good candidates for this test.

Gene

Official Gene Symbol OMIM ID
KMT5B 610881
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID

Related Test

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

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Bourgeron T. 2016. Comptes Rendus Biologies. 339: 300-7. PubMed ID: 27289453
  • Center for Disease Control and Prevention. 2014. Morbidity and Mortality Weekly Report. Surveillance Summaries (Washington, D.C. : 2002). 63: 1-21. PubMed ID: 24670961
  • De Rubeis S. et al. 2014. Nature. 515: 209-15. PubMed ID: 25363760
  • Iossifov I. et al. 2012. Neuron. 74: 285-99. PubMed ID: 22542183
  • Iossifov I. et al. 2014. Nature. 515: 216-21. PubMed ID: 25363768
  • Karam S.M. et al. 2015. American Journal of Medical Genetics. Part A. 167: 1204-14. PubMed ID: 25728503
  • Krumm N. et al. 2015. Nature Genetics. 47: 582-8. PubMed ID: 25961944
  • Lachner M., Jenuwein T. 2002. Current Opinion in Cell Biology. 14: 286-98. PubMed ID: 12067650
  • Larsen E. et al. 2016. Molecular Autism. 7: 44. PubMed ID: 27790361
  • Levy S.E. et al. 2009. Lancet. 374: 1627-38. PubMed ID: 19819542
  • McPartland J.C. et al. 2016. Encyclopedia of Mental Health. 2: 124-130.
  • Rhodes C.T. et al. 2016. Neuroepigenetics. 6: 10-25. PubMed ID: 27429906
  • Sanders S.J. et al. 2012. Nature. 485: 237-41. PubMed ID: 22495306
  • Stessman H.A. et al. 2017. Nature Genetics. 49: 515-526. PubMed ID: 28191889
  • Sztainberg Y., Zoghbi H.Y. 2016. Nature Neuroscience. 19: 1408-17. PubMed ID: 27786181
  • Wu H. et al. 2013. Febs Letters. 587: 3859-68. PubMed ID: 24396869
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TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  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.

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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.
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.

SPECIMEN TYPES
WHOLE BLOOD

(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.

DNA

(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.

CELL CULTURE

(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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