Primrose syndrome associated with unclassified immunodeficiency and a novel <i>ZBTB20</i> mutation

Yamamoto-Shimojima, Keiko; Imaizumi, Taichi; Akagawa, Hiroyuki; Kanno, Hitoshi; Yamamoto, Toshiyuki

doi:10.1002/ajmg.a.61432

Cited by 7 publications

(10 citation statements)

References 25 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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“…Alpha‐fetoprotein (AFP) levels showed that levels were typically elevated but not in all affected individuals, and did not show a marked change over time (Figure 2C). One patient showed selective IgG2 deficiency (P31) 18 . One patient developed a testis carcinoma at 27 years and a (fatal) seminoma in the other testis at 40 years of age 5 Another male developed a germ cell tumor at 28 years and also a seminoma at that age 9…”

Section: Resultsmentioning

confidence: 99%

“…No biochemical or genetic studies were performed specifically for the present study. We gathered data from 29 patients reported previously 1‐18 and 13 hitherto unpublished patients. One stillbirth was also included.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Primrose syndrome: Characterization of the phenotype in 42 patients

Melis¹,

Carvalho

Barbaro-Dieber

et al. 2020

Clinical Genetics

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Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels

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“…ZBTB20 , located at 3q13.31, has been identified as the causative gene for Primrose syndrome (MIM #259050), which is associated with severe neurodevelopmental disorders [ 30 ]. Previously, we found that the symptoms associated with neurodevelopmental disorders were very mild and inconsistent in the cases with 3q13 deletion compared to those observed in Primrose syndrome [ 31 ].…”

Section: Genes Whose Phenotypes Are Not Affected By Genomic Copy Number Changesmentioning

confidence: 99%

Genomic Aberrations Associated with the Pathophysiological Mechanisms of Neurodevelopmental Disorders

Yamamoto

2021

Cells

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Genomic studies are increasingly revealing that neurodevelopmental disorders are caused by underlying genomic alterations. Chromosomal microarray testing has been used to reliably detect minute changes in genomic copy numbers. The genes located in the aberrated regions identified in patients with neurodevelopmental disorders may be associated with the phenotypic features. In such cases, haploinsufficiency is considered to be the mechanism, when the deletion of a gene is related to neurodevelopmental delay. The loss-of-function mutation in such genes may be evaluated using next-generation sequencing. On the other hand, the patients with increased copy numbers of the genes may exhibit different clinical symptoms compared to those with loss-of-function mutation in the genes. In such cases, the additional copies of the genes are considered to have a dominant negative effect, inducing cell stress. In other cases, not the copy number changes, but mutations of the genes are responsible for causing the clinical symptoms. This can be explained by the dominant negative effects of the gene mutations. Currently, the diagnostic yield of genomic alterations using comprehensive analysis is less than 50%, indicating the existence of more subtle alterations or genomic changes in the untranslated regions. Copy-neutral inversions and insertions may be related. Hence, better analytical algorithms specialized for the detection of such alterations are required for higher diagnostic yields.

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Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation

Cited by 7 publications

References 25 publications

Mutations inZBTB20in individuals with persistent stuttering

Mutations inZBTB20in individuals with persistent stuttering

Primrose syndrome: Characterization of the phenotype in 42 patients

Genomic Aberrations Associated with the Pathophysiological Mechanisms of Neurodevelopmental Disorders

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