Helsmoortel-Van der Aa Syndrome via the ADNP Gene

Helsmoortel-Van der Aa syndrome (HVDAS) is a syndromic form of Autism Spectrum Disorders (ASD) that is associated with mild to severe intellectual disability (ID). To date all HVDAS patients present with ID and ASD, while a majority present with a thin upper lip (90%), prominent forehead with high hairline (75%) and ear malformations (70%). Hand abnormalities, vision defects, hypotonia, congenital heart defects, broad nasal bridge, smooth/long philtrum, mood disorders and seizures have been reported but vary among individuals (Krajewska-Walasek et al. 2016; Helsmoortel et al. 2014; Pescosolido et al. 2014).

ASD encompasses several neurodevelopmental disorders (such as HVDAS) characterized by varying degrees of social impairment, communication ability, and propensity for restricted interests and repetitive behavior(s) which usually present by age 3. Diagnosis is based on the degree and severity of symptoms and behaviors (Diagnostic and Statistical Manual of Mental Disorders (DSM-5); Levy et al. 2009; McPartland et al. 2016). Comorbidities occur in more than 70% of cases and include ID, epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi 2016).

ADNP (activity-dependent neuroprotective protein) is a transcriptional regulator that interacts with components of BAF (BRG1-associated factors) complexes to mediate chromatin remodeling and gene expression. Specifically, the C-terminal region of the ADNP protein interacts with the BAF complex proteins ARID1A, SMARCA4 and SMARCC2 (Helsmoortel et al. 2014; Mandel & Gozes 2007). Chromatin remodeling complexes like BAFs are essential for activity-dependent dendritic outgrowth and axonal development, a phenomenon that occurs in all neurons (Lessard et al. 2007).

Helsmoortel-Van der Aa is an autosomal dominant disorder resulting from almost exclusively de novo truncating variants that cause disease through a dominant-negative or haploinsufficient mechanism (Vandeweyer et al. 2014). The ADNP gene consists of 5-6 exons (depending on the transcript), but only the last 3 are translated. There are 9 zinc finger domains, a NAP domain which encodes a neuroprotectant peptide influencing neurodegeneration, DNA-binding homeobox domain, P*V*L motif that indirectly recognizes histone modifications through HP1α, and a C-terminal region which directly interacts with BAF complex proteins (Helsmoortel et al 2014; Vandeweyer et al. 2014).

To date, all truncating variants result in at least the loss of the last 166 residues from the ADNP C-terminus (Helsmoortel et al. 2014; Vandeweyer et al. 2014). One frameshift variant inherited from an unaffected parent has been reported in the NHLBI Exome Sequencing Project database. However, this variant truncates only the 5 carboxy terminal residues of the ADNP protein and likely does not disrupt the region involved in BAF complex interactions (Vandeweyer et al. 2014).

Genetic aberrations are reported to be responsible for 50-90% and 15-50% of ASD and ID cases, respectively (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). To date, 17 individuals with truncating variants in ADNP have been described in autism cohorts totaling ~7,000 individuals (Deciphering Developmental Disorders 2015; Helsmoortel et al. 2014; Krajewska-Walasek et al. 2016).

Currently, the contribution of de novo and inherited factors to Autism Spectrum Disorders risk is estimated to be approximately 50-60% (Krumm et al. 2015). ADNP is classified in the Simons Foundation Autism Research Initiative (SFARI) Database as a gene with ‘high confidence’ regarding ASD risk (https://gene.sfari.org/GeneDetail/ADNP). However, more than 700 genes total have been associated with ASD features (Bourgeron 2016). ADNP is estimated to be disrupted in 0.17% of all ASD cases, making it one of the most frequently implicated ASD genes to date (Helsmoortel et al. 2014).

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