Intellectual Disability/Autism Spectrum Disorders via the CHAMP1 Gene

Autism spectrum disorder (ASD) and intellectual disability (ID) are heterogeneous groups of neurodevelopmental disorders. ASD is characterized by varying degrees of social impairment, limited communication ability, propensity for repetitive behavior(s), and restricted interests (Levy et al. 2009. PubMed ID: 19819542). ID refers to significant impairment of cognitive and adaptive development (intelligence quotient, IQ<70) due to abnormalities of brain structure and/or function (American Association of Intellectual and Developmental Disabilities). ID is not a single entity, but rather a general symptom of neurologic dysfunction that is diagnosed before age 18 in 1%-3% of the population, irrespective of social class and culture (Kaufman et al. 2010. PubMed ID: 21124998; Vissers et al. 2016. PubMed ID: 26503795). In contrast, ASD symptoms usually present by age 3, and diagnosis is based on the degree and severity of symptoms and behaviors (McPartland et al. 2016). ASD and ID are highly comorbid, suggesting shared etiologies in many forms. For ASD specifically, comorbidities have been observed in more than 70% of cases, and include ID, epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi. 2016. PubMed ID: 27786181). 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 and ID (Bourgeron. 2016. PubMed ID: 27289453).

Pathogenic variants in CHAMP1 have been implicated as a monogenic cause of intellectual disability and global developmental delay. Individuals with loss of function variants present with developmental delay, ID, impaired motor abilities, short stature, severe speech impairment, muscular (truncal) hypotonia and orofacial hypotonia, hypertelorism, microcephaly, stereotypy, decreased pain sensation, neonatal feeding difficulties, hyperopia, and various subtle dysmorphic features (short philtrum, tented and everted lips, long face, pointed chin, low-set ears, up or down-slanting palpebral fissures). Other features reported in a minority of individuals include autism spectrum disorder, epilepsy/seizure, apneic episodes, choanal atresia, intestinal malrotation, bicuspid aortic valve, ventricular septal defects, a decrease in brain volume and white matter, and hearing loss. De novo loss of function variants have exclusively been reported in affected individuals (Tanaka et al. 2016. PubMed ID: 27148580; Hempel et al. 2015. PubMed ID: 26340335).

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. PubMed ID: 27790361; Karam et al. 2015. PubMed ID: 25728503). Incidence of ASD is approximately 1 in 68 individuals with a male-to-female ratio of 4:1 (Center for Disease Control 2014. PubMed ID: 24670961). De novo missense and loss of function variants are 15% and 75% more frequent in ASD patients than unaffected controls, respectively (Iossifov et al. 2014. PubMed ID: 25363768).

CHAMP1 pathogenic variants result in intellectual disability and global developmental delay symptoms in an autosomal dominant manner as all reported individuals are heterozygous for de novo loss of function variants. Copy number variants ranging in size from 966 kb to 12.77 Mb have been reported to encompass CHAMP1 with comparable clinical features. However, these copy number variants encompass multiple genes, and thus the specific role of CHAMP1 is unclear (Hempel et al. 2015. PubMed ID: 26340335).

The human CHAMP1 (chromosome alignment maintaining phosphoprotein 1) gene contains two 5’ untranslated exons and a third encoding an 812 amino acid protein. Specifically, the CHAMP1 protein consists of five C2H2 zinc finger domains (2 N-terminal and 3 C-terminal) flanking several SPE, WK, and FPE motifs. To date, de novo loss of function variants have been reported between the flanking N-terminal and C-terminal zinc finger domains (Tanaka et al. 2016. PubMed ID: 27148580). CHAMP1 expression has been observed in both fetal and adult tissue, with expression specifically reported during fetal brain development (Hawrylycz et al. 2012. PubMed ID: 22996553; Nagase et al. 2001. PubMed ID: 11347906; Tanaka et al. 2016. PubMed ID: 27148580).

CHAMP1 is important for proper chromosome alignment during metaphase. Specifically, the CHAMP1 FPE domains are necessary for the attachment of microtubules to the kinetochore complex, while the C-terminal zinc finger domains are important for protein localization to chromosomes and the mitotic spindle. CHAMP1 is also a component of the mitotic spindle assembly checkpoint complex, which monitors alignment of chromosomes at the metaphase plate and regulates the mitotic transition to anaphase (Itoh et al. 2011. PubMed ID: 21063390; Hempel et al. 2015. PubMed ID: 26340335; Tanaka et al. 2016. PubMed ID: 27148580). Defects in chromosome segregation resulting in variegated aneuploidies have been previously implicated in both syndromic and non-syndromic intellectual disability, microcephaly, and growth delay. Since all reported loss of function variants are predicted to disrupt the C-terminal zinc finger domains, disruption has been proposed as the mechanism behind dysmorphism and altered brain development observed in affected individuals (assuming a stable protein product is produced) (Hempel et al. 2015. PubMed ID: 26340335; Tanaka et al. 2016. PubMed ID: 27148580).

Genetic variants have been found responsible in 25-50% of Intellectual Disability (ID) cases, and this percentage increases proportionally with the severity of the phenotype (McLaren and Bryson. 1987. PubMed ID: 3322329). For autism spectrum disorders (ASD), while heritability estimates have been reported as high as 90% (Bailey et al. 1995. PubMed ID: 7792363; Lichtenstein et al. 2010. PubMed ID: 20686188), only 20% of cases can be explained to date using genetic approaches (Devlin and Scherer. 2012. PubMed ID: 22463983).

No single gene has been reported to account for more than 1% of all ASD cases to date (Hoang et al. 2018. PubMed ID: 28803755). Furthermore, large cohort studies of individuals with neurodevelopmental phenotypes have implicated hundreds of genes (Larsen et al. 2016. PubMed ID: 27790361; Bourgeron. 2016. PubMed ID: 27289453). Therefore, the clinical sensitivity of any single gene test with regard to a neurodevelopmental phenotype is expected to be low (≤1%).

This test provides full coverage of the single coding exon of the CHAMP1 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).