Heterozygous variants in <scp><i>ZBTB7A</i></scp> cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin

Lippe, Charlotte von der; Tveten, Kristian; Prescott, Trine; Holla, Øystein L.; Busk, Øyvind L.; Burke, Katherine; Sansbury, Francis H.; Baptista, Júlia; Fry, Andrew E.; Lim, Derek; Jolles, Stephen; Evans, Jennifer; Osio, Deborah; Macmillan, Carol; Bruno, Irene; Faltera, Flavio; Climent, Salvador; Urreitzi, Roser; Hoenicka, Janet; Palau, Francesc; Cohen, Ana S A; Engleman, Kendra; Zhou, Dihong; Amudhavalli, Shivarajan; Jeanne, Médéric; Bonnet‐Brilhault, Frédérique; Lévy, Jonathan; Drunat, Séverine; Derive, Nicolas; Haug, Marte G.; Thorstensen, Wenche Moe

doi:10.1002/ajmg.a.62492

Cited by 6 publications

(2 citation statements)

References 27 publications

(47 reference statements)

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“…BTB domains are known to be strong drivers of cotranslational assembly 59 , a process that lessens the likelihood of observing a disease mechanism other than loss of function 48 . Consistently, heterozygous variants in ZBTB7A have been linked to a neurodevelopmental phenotype and are suggested to cause loss of function 60 . While the gene has not yet been classified with a cancer role in the CGC, it is increasingly being recognised as a potential cancer driver 61 .…”

Section: Identification Of Novel Candidate Tumour Suppressors and Onc...mentioning

confidence: 82%

Protein structural context of cancer mutations reveals molecular mechanisms and identifies novel candidate driver genes

Pino,

Badonyi,

Semple

et al. 2024

Preprint

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Advances in structure determination and computational modelling are enabling us to study the protein structural context of human genetic variants at an unprecedented scale. Here, we investigate millions of human cancer-associated missense mutations in terms of their structural locations and predicted perturbative effects. We find that, while cancer-driving mutations have properties similar to other known disease-causing mutations, this is obscured by the abundance of passenger mutations in cancer sequencing datasets. Nevertheless, by considering the collective properties of mutations at the level of individual proteins, we identify distinct mutational signatures associated with tumour suppressors and oncogenes. Tumour suppressors are enriched in structurally damaging mutations, consistent with loss-of-function mechanisms. In contrast, oncogene mutations tend to be structurally mild, reflecting selection for gain-of-function driver mutations and against loss-of-function mutations. Although oncogenes are difficult to distinguish from genes with no role in cancer using only structural damage, we find that an alternate metric based on the clustering of mutations in three-dimensional space is highly predictive of oncogenes, particularly when mutation recurrence is considered. These observations allow us to identify novel candidate driver genes and speculate about their molecular roles, which we expect to have general utility in the analysis of cancer sequencing data.

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Section: Identification Of Novel Candidate Tumour Suppressors and Onc...mentioning

confidence: 82%

Protein structural context of cancer mutations reveals molecular mechanisms and identifies novel candidate driver genes

Pino,

Badonyi,

Semple

et al. 2024

Preprint

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“…25, 49, 50 Concomitantly, studies of rare individuals with substantially elevated HbF levels have revealed rare genetic variation at the β-globin gene locus and in other genes, including BCL11A , KLF1 , and ZBTB7A , which leads to more considerable increases in HbF levels. 6, 15, 51, 52 Here, by conducting the largest multi-ancestry GWAS of HbF levels to date we have uncovered new loci underlying variation in HbF levels, including the identification of BACH2 as a new genetically-nominated regulator of HbF. We have also defined how polygenic variation can interact with rare large-effect alterations to modify HbF levels in a population stratified across extremes of the HbF distribution.…”

Section: Discussionmentioning

confidence: 99%

Genetic regulation of fetal hemoglobin across global populations

Cato

et al. 2023

Preprint

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Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs in vivo. We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied BCL11A and HBS1L-MYB loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the HBB locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and β-thalassemia.

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Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data

Ferrer,

Duffy,

Olson

et al. 2024

Hum. Genet.

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Most rare disease patients (75 − 50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identi ed. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genetic databases to enable rapid review of genetic ndings. MethodsWe tested RENEW in an unselected cohort of 1,066 undiagnosed cases from the Mayo Clinic Center for Individualized Medicine using new information in ClinVar, HGMD and OMIM between the date of previous analysis/testing and April of 2022. Results5,741 variants prioritized by RENEW were rapidly reviewed by variant interpretation specialists. Mean analysis time was approximately 20 seconds per variant (32 hours total time). Reviewed cases were classi ed as: 879 (93.0%) undiagnosed, 63 (6.6%) putatively diagnosed, and 4 (0.4%) de nitively diagnosed. DiscussionNew strategies are needed to enable e cient review of genomic ndings in unsolved cases. We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process.

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Heterozygous variants in ZBTB7A cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin

Cited by 6 publications

References 27 publications

Protein structural context of cancer mutations reveals molecular mechanisms and identifies novel candidate driver genes

Protein structural context of cancer mutations reveals molecular mechanisms and identifies novel candidate driver genes

Genetic regulation of fetal hemoglobin across global populations

Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data

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