Intellectual Disability via the CRBN Gene

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD). Nonsyndromic ID is defined by the presence of intellectual disability as the sole clinical feature; however, often times the distinction between syndromic and nonsyndromic ID remains extremely difficult due to the subtle signs of syndromic ID (Kaufman et al. 2010. PubMed ID: 21124998).

Deficiency of cereblon (CRBN) protease leads to autosomal recessive mental retardation 2 (MRT2) (Xu et al. 2013. PubMed ID: 23983124). MRT2 can be nonsyndromic as well as syndromic and the variable clinical features include (but may not be limited to) intellectual disability, developmental delay, delayed or absent speech, motor delay, febrile seizures, intractable seizures, microcephaly, brain malformations, hypotonia, gait abnormalities, feeding difficulties, growth retardation, strabismus, cutaneous and genital anomalies, dysmorphic features such as synophris, hypotelorism, high nasal bridge, thin lips, micrognatia, high palate, large ears, smiling appearance and behavioral abnormalities including attention deficit hyperactivity disorder, aggressiveness, communication difficulties, and self-mutilating behavior (Higgins et al. 2000. PubMed ID: 10932263; Higgins et al. 2004. PubMed ID: 15151510; Higgins et al. 2004. PubMed ID: 15557513; Reuter et al. 2017. PubMed ID: 28097321; Papuc et al. 2015. PubMed ID: 25858704; Sheereen et al. 2017. PubMed ID: 28143899). Of note, at least one patient has been reported with abnormal levels of calcium and uric acids. Female patients tend to display a milder phenotype than males.

Mental retardation, autosomal recessive 2 (MRT2) is a neurodevelopmental disorder that results from biallelelic pathogenic variants in CRBN. CRBN consists of 11 coding exons, maps to chromosome 3p26.2, and encodes a 442 amino acid polypeptide. CRBN, primarily expressed in human hippocampus, is an ATP-dependent LON protease and a part of an E3 ubiquitin ligase complex CRL4^CRBN. CRBN contains a LON (DNA-binding ATP-dependent protease La) domain and a CULT (CRBN domain of unknown activity, binding cellular ligands and thalidomide) domain and is known to play a role in memory and learning by regulating the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels (Sheereen et al. 2017. PubMed ID: 28143899). To date, nonsense, missense and splice site pathogenic variants have been reported and there are also reports of gross duplications involving CRBN (Human Gene Mutation Database). The disease transmission pattern is consistent with autosomal recessive inheritance.

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795). We expect the analytical sensitivity of the CRBN single nucleotide variants to be high.

To date, two causative gross duplications involving CRBN have been reported (Papuc et al. 2015. PubMed ID: 25858704).

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