Brunner Syndrome via the MAOA Gene

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).

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).

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).

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. 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).