Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature

Abstract

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome. K E Y W O R D SDDD study, exome sequencing, intellectual disability, Primrose syndrome, ZBTB20

Expansion of the Primrose syndrome phenotype through the comparative analysis of two new case reports with ZBTB20 variants

“…In agreement, both variants reported here affect the second ZnF domain of ZBTB20 , within which several other disease‐associated variants have been reported. This supports the hypothesis that missense variants altering the wild‐type ZnF domains in ZBTB20 are more likely to affect protein structure and function and thus are more likely to be pathogenic than variants in other sites, such as the BTB domain (Cleaver et al, ).…”

“…PRIMS is caused by heterozygous missense variants in ZBTB20 . Over 60% of the variants reported are located in the ZnF domains of this gene, which are predicted to alter its binding affinity to DNA (Alby et al, ; Casertano et al, ; Cleaver et al, ; Cordeddu et al, ; Hersh et al, ; Mattioli et al, ). In agreement, both variants reported here affect the second ZnF domain of ZBTB20 , within which several other disease‐associated variants have been reported.…”

“…In 2014, Cordeddu and colleagues described heterozygous variants in ZBTB20 (most de novo) in eight patients previously diagnosed clinically with PRIMS. Thus far, there have been a total of 22 individuals with molecularly confirmed PRIMS reported in the literature (Alby et al, ; Casertano et al, ; Cleaver et al, ; Cordeddu et al, ; Grímsdóttir et al, ; Hersh et al, ; Mattioli et al, ; Stellacci et al, ).…”

Primrose syndrome: Characterization of the phenotype in 42 patients

“…Primrose syndrome (PS; MIM# 259050) is an infrequently described condition characterized by increased postnatal growth in height and head circumference, unusual facial features (frontal bossing, deeply set eyes, down‐slanting palpebral fissures), cognitive deficit associated with autism spectrum disorder, and ectopic calcifications 1 . With age, distal muscle atrophy, hearing loss, cataract, sparse body hair, and a disturbed glucose metabolism can become clear 2‐18 . Until recently most reported affected individuals have been adults as the phenotype may become more easily recognizable over time.…”

Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation

“…A ZBTB20 disruption due to a de novo balanced translocation has also been identified in a patient with similar clinical features (Rasmussen et al, ). Finally, in 2014, de novo mutations in ZBTB20 were identified in patients presenting clinical features of Primrose syndrome (Cordeddu et al, ) and additional patients with ZBTB20 mutations have been reported to date (Alby et al, ; Casertano et al, ; Cleaver et al, ; Grimsdottir et al, ; Mattioli et al, ; Stellacci et al, ). Thus, ZBTB20 was established as a gene responsible for Primrose syndrome and 3q13.31 deletion syndrome.…”