Xia-Gibbs Syndrome via the AHDC1 Gene

Pathogenic variants in the AHDC1 gene cause autosomal dominant Xia-Gibbs Syndrome. This disorder presents in infancy and is characterized by delayed psychomotor development (100%), mild to severe intellectual disability, absent or poor expressive speech (100%), hypotonia (90%), ataxia (65%), abnormal MRI findings (60%), autism (50%), and dysmorphic features (Jiang et al. 2018. PubMed ID: 29696776; Xia et al. 2014. PubMed ID: 24791903). Xia-Gibbs syndrome affects males and females in equal numbers, but males tend to be more severely affected with regard to speech and language abilities. Most patients gain the ability to walk independently, but about 60% never gain meaningful or diverse expressive language skills (<50 words). Features seen in less than half of affected individuals include sleep apnea (45%), strabismus (40%), short stature (40%), seizures (30%), poor vision (30%), and scoliosis (20%). Abnormal magnetic resonance imaging findings frequently include corpus callosum thinning, delayed myelination or leukomalacia, and cysts of the posterior fossa. Rarely, these brain abnormalities have been observed prenatally (He et al. 2019. PubMed ID: 31812316). Aggression or self-injury, craniosynostosis, failure to thrive, tracheomalacia, and the need for breathing support have been documented in less than 20% of affected individuals (Goyal et al. 2020. PubMed ID: 33520547). Dysmorphic features often include small, upturned earlobes, with ears appearing low-set or protuberant, deep-set eyes, up or down-slanting palpebral fissures, mild ptosis, esotropia, hypertelorism, flat nasal bridge, micrognathia, thin upper lip, and broad forehead. Despite the presence of facial similarities, a characteristic facial gestalt is not diagnostic of this condition (Jiang et al. 2018. PubMed ID: 29696776). Detection of a likely pathogenic or pathogenic early termination change in AHDC1 remains the only way to diagnose Xia-Gibbs syndrome.

Xia-Gibbs syndrome is a rare genetic disorder, with an estimated incidence of <1/1,000,000 and roughly 100 probands identified world-wide (Jiang et al. 2018. PubMed ID: 29696776; Goyal et al. 2020. PubMed ID: 33520547). The genetic causes of developmental delay and intellectual disability are extraordinarily diverse. A recent analysis of the top 99 most common single-gene causes of developmental delay identified AHDC1 in the top 40 (Top 99 Genetic Causes of Developmental Delay Panel). Thus, despite being rare, it is still one of the more common single-gene causes of psychomotor delay. While there is no treatment for this disorder, advantages of testing may include prognostic information, early identification and treatment of symptoms such as seizures, autism, short stature, and scoliosis as well as the ability to join relevant family support groups. Because all known pathogenic variants in this gene are sporadic, a confirmed de novo finding (implicating lower recurrence risk) may ease anxiety for future reproductive planning.

In addition to Xia-Gibbs syndrome, which is caused by early termination changes in AHDC1, there is some speculation that de novo or possibly even inherited missense changes in this gene may predispose to a milder phenotype (such as isolated autism; SFARI Gene). Additional research is needed to confirm this disease association, as currently few cases have been documented, and these phenotypes could be explained by other unknown genetic or environmental factors.

Xia Gibbs syndrome is an autosomal dominant disorder caused by pathogenic variants in the AHDC1 gene. A large majority of causative changes in AHDC1 are de novo early termination alterations (Jiang et al. 2018. PubMed ID: 29696776). The types of early termination changes include nonsense, frameshift, and large deletions (Jiang et al. 2018. PubMed ID: 29696776; Ritter et al. 2018. PubMed ID: 30152016; Wang et al. 2020. PubMed ID: 30615951). To our knowledge, no changes altering canonical splice sites have been identified as causative; however, they are absent from population databases of normal individuals, and would also be expected to be pathogenic (Human Gene Mutation Database). A single duplication including the entire AHDC1 gene has been reported as de novo in an individual with a phenotype consistent with Xia-Gibbs, suggesting that triplosensitivity may be an additional mechanism of disease that is not yet well established (Wang et al. 2020. PubMed ID: 30615951). De novo or inherited missense alterations in AHDC1 have been reported in patients who potentially have a milder or different form of Xia-Gibbs syndrome; however, the role of missense changes in this gene is not yet well established. Therefore, missense changes are of uncertain clinical significance. Several variants appear to be recurrent de novo alterations, with p. Cys791Trpfs*57 (c.2373_2374delTG) representing the causative variant in ~20% of cases (in unrelated patients), and p.Arg925* (c.2773C> T) and p.Gln970* (c.2908C> T) also recurring, but less frequently. Clinical phenotypes are variable, even for patients with the exact same genetic variant, highlighting the variable expressivity of this disorder. Constraint metrics in the gnomAD population database show that heterozygous loss of function changes are poorly tolerated, whereas missense changes are tolerated on the whole (Genome Aggregation Database). None of the documented pathogenic variants are present in the gnomAD population database of individuals without severe pediatric diseases. A single loss of function change (17 bp deletion) is reported in the heterozygous state in gnomAD in one individual (p.Phe761*), but the phenotype of this individual is unknown. Based on this information, and the fact that all reported pathogenic changes have occurred de novo, Xia-Gibbs is expected to be a fully penetrant genetic disorder, although germline mosaicism has been documented in at least one case (He et al. 2019. PubMed ID: 31812316).

The AHDC1 gene codes for the AT-Hook DNA-Binding Motif-Containing Protein 1, which is located on the short arm chromosome one at band p36 and is comprised of a single coding exon of 1603 amino acids. The function of the AHDC1 protein is largely unknown, but due to its domains and location, it is predicted to be a transcription factor with roles in DNA repair. It is found in the nucleus of cells, and is highly expressed in the brain, skeletal muscle, skin, and digestive tract (Uhlén et al. 2015. PubMed ID: 25613900). Model organisms analyzing the phenotype caused by knocking out this gene in other species have not been analyzed. AHDC1 has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

Pathogenic AHDC1 alterations span widely across the middle of the protein, and do not appear to be restricted to functional domains (Jiang et al. 2018. PubMed ID: 29696776). Currently, reported causative changes range between codons 262-1330. Specific genotype-phenotype correlations have not yet been established for AHDC1, and such correlations are less typical for diseases resulting exclusively from early termination changes, like Xia-Gibbs syndrome.

Pathogenic variants in AHDC1 are expected to account for <0.1% of cases of early neurodevelopmental delays. In this context, it is important to note the extraordinarily broad genetic heterogeneity for neurodevelopmental delay and intellectual disability phenotypes (McRae et al. 2017. PubMed ID: 28135719; Bowling et al. 2017. PubMed ID: 28554332). Testing a large panel of genes as well as using a trio approach (testing parents along with the proband) is known to have higher diagnostic yield due to the extreme clinical and genetic heterogeneity of these phenotypes (Vissers et al. 2016. PubMed ID: 26503795).

Early termination changes (nonsense SNVs and small or large deletions and duplications) are the only variant types known to cause Xia-Gibbs syndrome (Jiang et al. 2018. PubMed ID: 29696776; Human Gene Mutation Database); therefore, this test’s analytical sensitivity for AHDC1 pathogenic changes is expected to be very high. In summary, this test is expected to detect the vast majority of pathogenic changes in AHDC1.

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the AHDC1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).