ZBTB20 – Primrose syndrome

Primrose syndrome (MONDO:0009798) is a rare autosomal dominant neurodevelopmental disorder characterized by macrocephaly, distinctive facial dysmorphism, intellectual disability, and variable multisystem involvement. The causal gene, ZBTB20, was first implicated through heterozygous de novo missense variants in 2016, and subsequent cohorts have reinforced this association (PMID:27061120).

Inheritance is exclusively autosomal dominant with all pathogenic ZBTB20 variants confirmed as de novo by trio testing in unrelated probands (PMID:30637921; PMID:32266967). No pedigree-based segregation has been observed beyond the de novo occurrences.

To date, 42 unrelated individuals have been reported with de novo ZBTB20 variants (PMID:32266967). The variant spectrum is dominated by missense changes clustering in the C2H2 zinc-finger domains (e.g., c.1931C>T (p.Thr644Ile)), with fewer truncating alleles (nonsense and frameshift) reflecting allelic heterogeneity (PMID:29737001).

Clinical features are highly concordant: intellectual disability (100%), macrocephaly (72%), sensorineural hearing loss (83%), hypotonia (78%), and hypoplasia of the corpus callosum (>90% on MRI) are core findings (PMID:30637921; PMID:32266967). Additional manifestations include sparse body hair, distal muscle wasting, ear cartilage calcifications, and metabolic disturbances.

Functional assays demonstrate that ZBTB20 pathogenic variants exert dominant-negative effects on transcriptional repression. In vitro studies of missense and truncating alleles show loss of repression activity, while Zbtb20 knockout mice manifest growth retardation and metabolic dysfunction consistent with human phenotypes (PMID:29737001; PMID:19273596). These data support a dominant-negative/haploinsufficiency mechanism.

No conflicting evidence has been reported that disputes the ZBTB20–Primrose syndrome relationship. The reproducibility of de novo findings across multiple centers and functional concordance underpins a definitive gene–disease classification.

Overall, robust genetic and experimental evidence establishes ZBTB20 as the causative gene for Primrose syndrome, guiding molecular diagnosis and enabling early intervention for associated neurodevelopmental and metabolic features. Key take-home: consider ZBTB20 de novo variant testing in patients with intellectual disability, macrocephaly, and hearing loss to facilitate prompt clinical management.

References

• American journal of medical genetics. Part A | 2016 | Novel de novo mutations in ZBTB20 in Primrose syndrome with congenital hypothyroidism. PMID:27061120
• Clinical genetics | 2020 | Primrose syndrome: Characterization of the phenotype in 42 patients. PMID:32266967
• American journal of medical genetics. Part A | 2019 | Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature. PMID:30637921
• Human mutation | 2018 | Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome. PMID:29737001
• Molecular and cellular biology | 2009 | Zinc finger protein Zbtb20 is essential for postnatal survival and glucose homeostasis. PMID:19273596

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