Primrose Syndrome via the ZBTB20 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).

Primrose syndrome (PRIMS) is a form of syndromic ID that is caused by the deficiency of Zinc finger and BTB-domain containing protein ZBTB20. The clinical features of PRIMS may include (but may not be limited to) cognitive and motor delay, intellectual disability, hypotonia, short stature, obesity, macrocephaly, brachycephaly, schizophrenia, behavioral abnormalities such as autism, tics, phobias, self-injurious behavior, repetitive compulsive movements, restlessness, aggressiveness, and variable anomalies of the head, neck, skin, hair, nail as well as genitourinary and skeletal systems, including wide forehead, large jaw, midface hypoplasia, large calcified pinnae, hearing loss, cataract, ptosis, deep-set eyes, small and downturned mouth, narrow chest, joint contractures, osteoporosis, distal muscle wasting, dysmorphic toe nails and fingernails, and sparse scalp hair (Mathijssen et al. 2006. PubMed ID: 16530709; Dalal et al. 2010. PubMed ID: 20644156; Carvalho and Speck-Martins. 2011. PubMed ID: 21567911). Of note, some features may be progressive (Primrose. 1982. PubMed ID: 6809950), and there is at least one report of germ cell tumor development (Mathijssen et al. 2006. PubMed ID: 16530709). Affected individuals have also been reported with congenital hypothyroidism, hypergonadotrophic hypogonadism and insulin-resistant diabetes mellitus in adulthood (Dalal et al. 2010. PubMed ID: 20644156, Posmyk et al. 2011. PubMed ID: 21910247).

Primrose syndrome is an autosomal dominant disorder, caused by pathogenic variants (primarily de novo) in human gene Zinc finger and BTB-domain containing protein 20 (ZBTB20). ZBTB20 maps to chromosome 3q13.31 and consists of 4 coding exons that translate into a 741 amino acid polypeptide. ZBTB20 is a member of the POK (POZ and Kruppel) family of transcriptional repressors that interact with DNA via their conserved C2H2 Kruppel-type zinc finger and BTB/POZ domains (Sutherland et al. 2009. PubMed ID: 19273596). ZBTB20 protein is hypothesized to play important role in growth, glucose homeostasis and detoxification. To date, primarily missense variants have been reported in human ZBTB20 gene (Human Gene Mutation Database).

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). Analytical sensitivity should be high because the majority of pathogenic variants reported within this gene to date are detectable by sequencing. To date, 4 gross deletions and complex rearrangements involving ZBTB20 have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the ZBTB20 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).