X-Linked Intellectual Disability Panel

Intellectual Disability (ID) is diagnosed in 1-3% of the total population, and X-linked genes account for 5-10% of ID cases in males (Vissers et al. 2016. PubMed ID: 26503795; Kaufman et al. 2010. PubMed ID: 21124998; Lubs et al. 2012. PubMed ID: 22482801; Tzschach. 2015. PubMed ID: 25649377). X-linked intellectual disability (XLID) is phenotypically diverse, ranging from severe early-onset syndromic diseases involving multiple systems, to mild or isolated (non-syndromic) forms (Neri et al. 2018. PubMed ID: 29696803).

While true treatments are often limited for XLID disorders, advantages of testing and molecular diagnosis are still numerous. These include prognostic information, early identification and treatment of symptoms (autism, seizures, other comorbidities), and ability to join condition-specific support groups. When parental inheritance is observed, families can use this information for future family planning (including prenatal testing or pre-implantation genetic diagnosis). Alternatively, if a patient has a confirmed de novo variant (undetectable in parents), this may ease anxiety for the family, due to the dramatically reduced recurrence risk.

X-linked intellectual disability occurs in both X-linked dominant and X-linked recessive inheritance patterns. Males are disproportionately affected with X-linked recessive (XLR) forms of XLID due to hemizygosity of the X-chromosome, while several factors affect disease presentation in females. One of these factors is skewed patterns of X-chromosome inactivation in females, which can impact disease severity or alter presenting symptoms (Plenge et al. 2002. PubMed ID: 12068376; Fieremans et al. 2016. PubMed ID: 27159028). In cases where inactivation is skewed completely toward the mutated allele, an XLR disorder may present similarly in a female to that seen in male. Alternatively, skewing toward the normal allele or tissue specific patterns of skewing may cause female carriers of an X-linked dominant disorder to present with significantly milder or variable presentations. The cellular mosaicism resulting from random X-inactivation in females is proposed as the mechanism for one female-limited form of XLID, caused by pathogenic variation in the PCDH19 gene (Dibbens et al. 2008. PubMed ID: 18469813). Another factor affecting gender-skewing in X-linked disorders is early lethality in males for some X-linked diseases, leading to these disorders appearing to disproportionately affect females (Franco et al. 2006. PubMed ID: 16650755).

This panel focuses on genes associated with established monogenic forms of XLID (Neri et al. 2018. PubMed ID: 29696803). A wide variety of causative variant types in these genes have been reported to cause XLID (including missense, nonsense, splicing, frameshift, large insertions and deletions, complex rearrangements, and trinucleotide repeat expansions)(Human Gene Mutation Database). Causative XLID variants in males are frequently inherited from an unaffected or mildly affected mother; yet, de novo mutations are another common cause of XLID in both males and females.

Pathogenic variants in over 140 genes have been associated with XLID (Neri et al. 2018. PubMed ID: 29696803). As such, XLID genes represent ~15% of the total genes currently known to cause intellectual disability (ID) in humans (Neri et al. 2018. PubMed ID: 29696803). We estimate this panel will identify pathogenic variants in 20-40% of patients with a strong family history of X-linked intellectual disability (XLID), who are fragile-X negative. Increased diagnostic yield is observed for syndromic cases, while lower rates are observed for isolated or nonsyndromic ID (de Brouwer et al. 2007. PubMed ID: 17221867; Hu et al. 2016. PubMed ID: 25644381; Chiurazzi and Pirozzi. 2016. PubMed ID: 27127621). Due to the high genetic heterogeneity of ID, testing a large panel of genes is known to have a higher diagnostic yield; therefore, whole exome (or genome) sequencing should be considered for all patients with intellectual disability as a primary presenting symptom (Vissers et al. 2016. PubMed ID: 26503795). This test will detect both large copy number variants (CNVs) as well as smaller sequence variants with high analytical sensitivity. Detection of trinucleotide repeat expansions (as seen in fragile X syndrome) requires a different test.

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

This panel typically provides 98.9% coverage of all coding exons of the genes 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 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).

Genes of this panel that typically get low coverage in an area of high pathogenic variation include (but are not necessarily limited to): ABCD1, IKBKG, and RPS6KA3. If a disorder associated with one of these genes is suspected, additional testing may be warranted. Special care is taken to obtain full coverage of the ARX gene on this panel. For two ARX exons where NGS coverage is typically poor (exons 2 and 5), we perform routine Sanger sequencing.

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).