Syndromic X-linked intellectual Disability Type 34, via the NONO Gene

Pathogenic variants in the NONO gene cause syndromic X-linked intellectual disability (XLID), type 34. This disorder is male-limited and presents in infancy with global developmental delay—including hypotonia, motor delays, cognitive deficits, and speech delay. Initial brain scans often appear normal; however, most patients develop dysplasia of the corpus callosum and some develop other central nervous system abnormalities, including cerebellar defects. Many people with this disorder learn to crawl or walk with ataxia, and can also develop language abilities over time. Physically, individuals with pathogenic NONO variants have a slender build, relative macrocephaly, and frontal bossing. Congenital heart defects are also common, notably left ventricular non-compaction cardiomyopathy (LVNC), as well as right ventricular hypertrophy, patent foramen ovale, patent ductus arteriosus, and atrial or ventricular septal defects. Some patients have early difficulties with feeding or breathing, requiring medical support. Behaviorally, these individuals are usually characterized as shy and anxious, though cheerfulness, autism, impulsiveness, aggressiveness, and hyperactivity have also been reported. Facial dysmorphism is variable, but can include strabismus, hypertelorism, epicanthal folds, long face, malar hypoplasia, prominent nose, short philtrum, and open mouth. Other minor features of this disorder are cryptorchidism, joint hyperreflexia, joint hyperlaxity, kyphosis, scoliosis, plagiocephaly, fifth finger clinodactyly, pes planus, hallux valgus, long narrow hands and feet, sleep apnea, myopia, café au lait macules, accessory nipples, and intention tremor (Mircsof et al. 2015. PubMed ID: 26571461, Reinstein et al. 2016. PubMed ID: 27329731, Scott et al. 2017. PubMed ID: 27550220).

While there are no treatments for NONO-related intellectual disability syndrome, patients and their families may benefit from a molecular diagnosis for prognostic information, early identification and treatment of symptoms, or for connecting with NONO-related XLID support groups. For reproductive planning, families can get maternal testing to determine if a variant arose de novo in the proband, or is present in the maternal germline.

NONO-related intellectual disability syndrome is inherited in an X-linked recessive pattern, and to date only males have been characterized. Roughly half of the pathogenic NONO variants are inherited from unaffected mothers and the others arise de novo (Mircsof et al. 2015. PubMed ID: 26571461, Reinstein et al. 2016. PubMed ID: 27329731, Scott et al. 2017. PubMed ID: 27550220). Carrier females do not express any apparent features of the disorder; however, it is important to note that the total numbers of patients identified is still very small (less than 10 documented in the literature). Therefore, the possibility of affected females (perhaps due to skewed X-inactivation) has not yet been thoroughly explored.

NONO is a non-POU domain-containing octamer-binding gene located at Xq13.1. NONO encodes a nucleic acid binding protein involved in RNA transcriptional regulation, splicing, nuclear retention, and transport (www.genecards.org, Stelzer et al. 2016. PubMed ID: 27322403). Pathogenic variants include nonsense, frameshift, canonical splice, non-canonical splice, and large deletions. Functional studies show that little or no NONO protein is produced from these altered transcripts, indicating a loss of function mechanism of disease (Mircsof et al. 2015. PubMed ID: 26571461, Scott et al. 2017. PubMed ID: 27550220). The small causative variants are all located in the latter half of the protein, including in the last exon (Reinstein et al. 2016. PubMed ID: 27329731). One large deletion includes coding exons 1-3 (Scott et al. 2017. PubMed ID: 27550220). Two pathogenic NONO variants have been observed more than once—namely a nonsense alteration at amino acid 365, and a frameshift beginning at amino acid 466. The differential diagnosis for NONO XLID is quite broad because the presenting features can be general. Pathogenic NONO variants are expected to have 100% penetrance in males.

The diagnostic yield of this test for males with syndromic intellectual disability is predicted to be very low (<0.1%), however no large cohorts estimating clinical sensitivity have been published for this gene. It is important to note the high clinical and genetic heterogeneity of intellectual disability, and improved diagnostic yields that result from testing large panels of genes as well as testing parents along with the patient using a trio approach. The analytical sensitivity of this test is expected to be high, as it will detect all types of NONO variants identified to date, including sequence variants as well as multiple-exon deletions or duplications in this gene.

Additional Sanger sequencing is performed for regions not captured or with insufficient numbers of sequence reads.

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