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

Ferreira, Laura Durão; Borges-Medeiros, Rayssa L.; Thies, Jenny; Schnur, Rhonda E.; Lam, Christina; Oliveira, João Ricardo Mendes de

doi:10.1002/ajmg.a.61297

Cited by 5 publications

(5 citation statements)

References 16 publications

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“…Here we have performed additional linkage analyses as well as whole exome, whole genome, and Sanger sequencing, which revealed a unique rare homozygous coding variant in ZBTB20 (MIM: 606025) that co-segregates with stuttering in this family. Although no individuals with homozygous mutations in ZBTB20 have previously been observed, heterozygous mutations have been associated with Primrose syndrome, a rare multisystem developmental disorder [14,15,16,17,18,19,20,21,22,23]. ZBTB20, also known as DPZF [24], HOF [25], or ZNF288 is a member of the POK (POZ and Krüppel) family of transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Mutations inZBTB20in individuals with persistent stuttering

Frigerio-Domingues

Raza

Han

et al. 2022

Preprint

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Background: Previous studies identified a strong linkage signal for non-syndromic persistent developmental stuttering on chromosome 3q13.2-3q13.33 in a large consanguineous family of Pakistani origin. To identify the causative genetic variant at this locus, we performed further analysis, including whole exome, whole genome, and targeting Sanger sequencing. Results: We identified a homozygous rare c.2155G>A variant in ZBTB20 in individuals who stutter. This mutation encodes Isoleucine in place of a highly conserved Valine at amino acid position 719 in ZBTB20 that co-segregates (LOD = 4.23) with stuttering under a model of recessive inheritance with reduced penetrance in this family. Coding variants in this gene were significantly more frequent in a multiethnic cohort of unrelated individuals who stutter than in individuals in large population databases comprised of our normal control subjects and gnomAD database subjects matched for ethnicity. ZBTB20 encodes a zinc-finger transcription factor, and luciferase reporter constructs using genes known to be regulated by ZBTB20 showed that the Ile719 mutant form of the protein displays altered transcriptional regulation in vitro. Although homozygosity for mutations in ZBTB20 has not previously been observed, dominant mutations in ZBTB20 have been reported in Primrose syndrome, a rare Mendelian dominant disorder characterized by tall stature, developmental delay, dysgenesis of the corpus callosum, but generally not speech disorders. Clinical re-examination of the affected family members ten years after their original ascertainment revealed only some suggestive signs associated with Primrose syndrome. Conclusions: Our findings support variants in ZBTB20 as a cause of stuttering in a large family, and rarely in the wider population. Previous studies in mice have demonstrated that Zbtb20 is required for the development of astrocytes, a brain cell type previously implicated in an animal model of stuttering. Our findings support our hypothesis that astrocyte pathology is involved in this disorder. Our findings also broaden the medical genetic view of disorders of ZBTB20, and demonstrate that individuals carrying a homozygous mutation in this gene can be viable, and that they can primarily display persistent developmental stuttering.

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Section: Introductionmentioning

confidence: 99%

Mutations inZBTB20in individuals with persistent stuttering

Frigerio-Domingues

Raza

Han

et al. 2022

Preprint

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“…Primrose syndrome is a very rare disorder characterized by intellectual and behavioral disabilities associated with other physical signs such as ear lobe calcification, macrocephaly, and dysmorphic facial features. 6 Symptoms of this disorder may appear during childhood, 7 but the diagnosis is identified in adulthood in the majority of cases. 5 There is no previous article in the literature that discusses the prenatal diagnosis of Primrose syndrome and reports its sonographic prenatal features.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Diagnosis of Primrose Syndrome

Abdallah,

Spaggiari,

Brisset

et al. 2023

J of Ultrasound Medicine

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Primrose syndrome is a very rare congenital malformation. Symptoms of this disorder may appear during childhood, but the diagnosis is identified in adulthood in the majority of cases. The prenatal diagnosis of Primrose syndrome is not developed in the literature. We present herein a case series of 3 cases with characteristic sonographic features. A dysmorphic metopic suture, downslanting palpebral fissures, a wide forehead, and agenesis of corpus callosum are the main signs. A missense mutation in ZBTB20 identified in whole exome sequencing can confirm the prenatal diagnosis of Primrose syndrome.

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“…We believe that in the future, as genetic testing technology matures, more and more patients will be diagnosed in childhood and adolescence, allowing for early intervention and improved prognosis. There are no standard clinical treatment protocols for this disease, but the treatment is tailored to the individual, and Laura D. Ferreira et al reported that one child was treated with risperidone, but the results were poor (Ferreira et al, 2019). In addition, genetic screening of the couple and calculation of the genetic risk of the offspring in combination with the genetic screening results are the most effective preventive tools available for the disease.…”

Section: Discussionmentioning

confidence: 99%

Novel de novo mutation in ZBTB20 in a Chinese Primrose syndrome family and a review of the literature

Li,

Zhang,

Tian

et al. 2023

Molec Gen & Gen Med

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BackgroundPrimrose syndrome is an autosomal dominant disorder characterized by craniofacial dysmorphism, mental retardation, developmental delay, progressive muscle atrophy and calcification of the earlobe due to a mutation in the ZBTB20.MethodWe reported a case of a Chinese boy with clinical symptoms resembling Primrose Syndrome, and performed genetic etiology analysis of the proband's family through Trio whole exome sequencing.ResultA novel missense variant c.1927T>A(p.F643I) in exon 14 of the ZBTB20 (NM_001348803) was identified in the proband. This is the first report case of primrose syndrome in China, and our case extends the variant spectrum of ZBTB20 and further strengthens the understanding of primrose syndrome.ConclusionHowever, there are no formal clinical guidelines for the management of this disease, and research on treatment and prognosis remains a challenge and focus in future.

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

Cited by 5 publications

References 16 publications

Mutations inZBTB20in individuals with persistent stuttering

Mutations inZBTB20in individuals with persistent stuttering

Prenatal Diagnosis of Primrose Syndrome

Novel de novo mutation in ZBTB20 in a Chinese Primrose syndrome family and a review of the literature

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