Brunner Syndrome via the MAOA 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
10697 MAOA 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
10697MAOA81479 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.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

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

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Brunner syndrome is a rare neurodevelopmental disorder characterized by intellectual disability, autism spectrum disorder (ASD), and impulsive, aggressive behavioral outbursts trigged by a reaction to stress. Individuals also present with reduced 5-hydroxyindolacetic acid (5-HIAA, a metabolite of serotonin), homovanillic acid (HVA), and vanillylmandelic acid (VMA), and increased serotonin levels in urine (Brunner et al. 1993. PubMed ID: 8211186; Palmer et al. 2016. PubMed ID: 25807999; Bortolato et al. 2018. PubMed ID: 29748850). In at least one family, aggressive outbursts have been associated with the consumption of foods and drinks high in tyramine (beer, cheese, foods with yeast extract). Symptoms were ameliorated by treatment with a selective serotonin reuptake inhibitor (SSRI) and dietary restriction of tyramine. As such, SSRIs have been suggested as a treatment option for some individuals with Brunner syndrome (Palmer et al. 2016. PubMed ID: 25807999).

Features of Brunner syndrome have also been reported with other neurodevelopmental disorders having additional clinical features. These include MAO deletion syndrome (sudden loss of muscle tone) and atypical Norrie disease (congenital blindness) (Saito et al. 2014. PubMed ID: 23414621; Bortolato et al. 2018. PubMed ID: 29748850).

ASD encompasses 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. PubMed ID: 19819542). 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. PubMed ID: 27786181). Recent studies using whole exome trios have identified novel gene candidates, with familial and de novo variants from several hundred genes now implicated in the development of ASD (Bourgeron. 2016. PubMed ID: 27289453).

Genetics

Pathogenic variants in the X-linked MAOA gene cause Brunner syndrome. Missense, nonsense, and frameshift variants inherited by affected males from their carrier mothers have been exclusively reported (no de novo cases have been reported). Females heterozygous for MAOA pathogenic variants do not present with the hallmark behavioral features of Brunner syndrome (Bortolato et al. 2018. PubMed ID: 29748850). Multi-gene deletions including MAOA have been reported in individuals presenting with MAO deletion syndrome (deletion of both monoamine oxidases, MAOA and MAOB) and atypical Norrie disease (deletion of MAOA, MAOB, and NDP) (Saito et al. 2014. PubMed ID: 23414621; Suárez-Merino et al. 2001. PubMed ID: 11385715; Bortolato et al. 2018. PubMed ID: 29748850).

MAOA (monoamine oxidase A) encodes one of two monoamine oxidases that catalyze the metabolism of neurotransmitters including dopamine, norepinephrine, serotonin, and minor amines such as tyramine (Palmer et al. 2016. PubMed ID: 25807999; Bortolato et al. 2018. PubMed ID: 29748850; Saito et al. 2014. PubMed ID: 23414621). Buildup of these compounds can be neurotoxic, and defects in their metabolism have been suggested to impact behavior (Bortolato et al. 2018. PubMed ID: 29748850; Brunner et al. 1993. PubMed ID: 8211186). Mutant forms of MAOA may selectively metabolize certain neurotransmitters more effectively than others. For example, build-up of serotonin (resulting in serotonin syndrome features) has been reported in some, but not all individuals with Brunner syndrome (Palmer et al. 2016. PubMed ID: 25807999; Nandigama et al. 2001. PubMed ID: 11732903).

Testing Strategy

This test provides full coverage of all coding exons of the MAOA 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV PGxome

Only a handful of individuals have been identified with Brunner syndrome despite widespread screening of X-linked intellectual disability cohorts, suggesting it is a rare X-linked disorder (Bortolato et al. 2018. PubMed ID: 29748850; Brunner et al. 1993. PubMed ID: 8211186; Palmer et al. 2016. PubMed ID: 25807999). Since this test covers all protein coding exons of MAOA, its analytical sensitivity to detect protein truncating or missense variants is presumed to be nearly 100%.

With respect to autism spectrum disorder (ASD) phenotypes, genetic evaluation of ASD patients is estimated to identify a cause in up to 40% of cases. The combined diagnostic yield of chromosomal microarray testing and FMR1 CGG-repeat expansion testing is approximately 11%-15% (Schaefer and Mendelsohn. 2013. PubMed ID: 23519317). The role of nucleotide substitutions and small insertions/deletions in autism-related genes is less clear, but may be as high at 15%, depending on the penetrance of the candidates (Schaefer and Mendelsohn. 2013. PubMed ID: 23519317; Casanova et al. 2016. PubMed ID: 26985359). To date, almost 1,000 genes have documented associations with ASD. It has been reported that nearly 60% of the total variation occurs in approximately 200 genes each of which have several ASD-associated variants (Stenson et al. 2014. PubMed ID: 24077912).

Indications for Test

Individuals diagnosed with Brunner syndrome or those presenting with behavioral anomalies and an abnormal urine profile are good candidates for this test. A panel (or exome/genome) sequencing test would nearly always be more appropriate for patients with ASD, behavioral, or neurodevelopmental disorder features, unless previous clinical knowledge of features implicates the MAOA gene. For example, a symptomatic male with affected male siblings or maternal uncles having a known MAOA pathogenic variant and/or clinical features may consider MAOA testing (targeted Sanger sequencing for the known variant may be most appropriate).

Gene

Official Gene Symbol OMIM ID
MAOA 309850
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Monoamine Oxidase A Deficiency XL 300615

Citations

  • Bortolato et al. 2018. PubMed ID: 29748850
  • Bourgeron. 2016. PubMed ID: 27289453
  • Brunner et al. 1993. PubMed ID: 8211186
  • Casanova et al. 2016. PubMed ID: 26985359
  • Levy et al. 2009. PubMed ID: 19819542
  • McPartland et al. 2016.
  • Nandigama et al. 2001. PubMed ID: 11732903
  • Palmer et al. 2016. PubMed ID: 25807999
  • Saito et al. 2014. PubMed ID: 23414621
  • Schaefer and Mendelsohn. 2013. PubMed ID: 23519317
  • Stenson et al. 2014. PubMed ID: 24077912
  • Su├írez-Merino et al. 2001. PubMed ID: 11385715
  • Sztainberg and Zoghbi. 2016. PubMed ID: 27786181

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.

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

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