Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome

Walz, Katherina; Cohen, Devon; Neilsen, Paul M.; Foster, I I Joseph; Brancati, Francesco; Demir, Korcan; Fisher, Richard; Moffat, M.F.; Verbeek, Nienke E.; Bjørgo, Kathrine; Castro, Adriana Lo; Curatolo, Paolo; Novelli, Giuseppe; Abad, Clemer; Cao, Lei; Zhang, Lily; Diaz‐Horta, Oscar; Young, Juan I.; Callen, David F.; Tekin, Mustafa

doi:10.1007/s00439-014-1509-2

Cited by 53 publications

(126 citation statements)

References 25 publications

(43 reference statements)

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“…P7 has a typical KBG phenotype, and the p.Arg2512Trp vari-ant arose de novo affecting a conserved amino acid. Furthermore, a previously reported patient has a missense variant affecting the same amino acid position (p.Arg2512Gln) [Walz et al, 2015]. Thus, we believe that this variant is pathogenic and that an Arginine in position 2512 is likely fundamental for ANKRD11 function.…”

Section: Discussionmentioning

confidence: 99%

Novel Mutations and Unreported Clinical Features in KBG Syndrome

Scarano¹,

Tassone²,

Graziano

et al. 2019

Mol Syndromol

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KBG syndrome is an autosomal dominant disorder caused by pathogenic variants within ANKRD11 or deletions of 16q24.3 which include ANKRD11. It is characterized by distinctive facial features, developmental delay, short stature, and skeletal anomalies. We report 12 unrelated patients where a clinical diagnosis of KBG was suspected and confirmed by targeted analyses. Nine patients showed a point mutation in ANKRD11 (none of which were previously reported) and 3 carried a 16q24.3 deletion. All patients presented with typical facial features and macrodontia. Skeletal abnormalities were constant, and the majority of patients showed joint stiffness. Three patients required growth hormone treatment with a significant increase of height velocity. Brain malformations were identified in 8 patients. All patients showed behavioral abnormalities and most had developmental delay. Two patients had hematological abnormalities. We emphasize that genetic analysis of ANKRD11 can easily reach a detection rate higher than 50% thanks to clinical phenotyping, although it is known that a subset of ANKRD11-mutated patients show very mild features and will be more easily identified through the implementation of gene panels or exome sequencing. Joint stiffness was reported previously in few patients, but it seems to be a common feature and can be helpful for the diagnosis. Hematological abnormalities could be present and warrant a specific follow-up.

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Section: Discussionmentioning

confidence: 99%

Novel Mutations and Unreported Clinical Features in KBG Syndrome

Scarano¹,

Tassone²,

Graziano

et al. 2019

Mol Syndromol

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“…The Exome Aggregration Consortium (ExAC) probability of loss-of-function (LOF) intolerance (pLI) score was calculated to be 1.0, indicating that this gene is very intolerant to mutations, and previous studies have indicated that mutations in this gene often lead to haploinsufficiency (see Discussion) (Lek et al 2016b). Other mutations in this gene have been previously identified as contributing to KBG syndrome, a rare disease that affects around 60 to 70 people worldwide (Brancati et al 2006; Sirmaci et al 2011; Crippa et al 2015; Walz et al 2015). The presence of the mutation was confirmed using Sanger sequencing (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Here we report our efforts in phenotypic characterization and molecular diagnosis of a previously undiagnosed pediatric patient. We report the identification of a de novo mutation in ANKRD11 , which led to the recognition of KBG syndrome (Ockeloen et al 2015; Walz et al 2015) in the sequenced proband. KBG syndrome (OMIM #148050) is a rare, but increasingly recognized, autosomal dominant genetic condition.…”

Section: Introductionmentioning

confidence: 99%

KBG syndrome involving a single-nucleotide duplication in ANKRD11

Kleyner

Malcolmson

Tegay

et al. 2016

Cold Spring Harb Mol Case Stud

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KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis. Subsequent exome sequencing identified a novel de novo heterozygous single base pair duplication (c.6015dupA) in ANKRD11, which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in ANKRD11, thereby implicating it as contributing to the proband's symptoms and yielding a molecular diagnosis of KBG syndrome. Before molecular diagnosis, this syndrome was not recognized in the proband, as several key features of the disorder were mild and were not recognized by clinicians, further supporting the concept of variable expressivity in many disorders. Although a diagnosis of cerebral folate deficiency has also been given, its significance for the proband's condition remains uncertain.

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“…We selected the five ANKRD11 variants observed in our patients for functional evaluation and found one abolish ANKRD11 protein abundance, which pointed to the possibility that reduced ANKRD11 protein level contributes to OC onset, consistent with prior observed effect of ANKRD11 level in breast cancer. [29][30][31] Further functional experiment will be needed to characterize the effect of other deleterious ANKRD11 variants such as G2480R, which sits in the C-terminal of ANKRD11 responsible for signaling ANKRD11 degradation, 32 as well as to investigate their potential functional consequence on cell proliferation, invasion and migration in order to understand the mechanism underneath the observed increased risk of OC.…”

Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

Zhu

Zhang

Chen

et al. 2019

Intl Journal of Cancer

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Despite the identification of several ovarian cancer (OC) predisposition genes, a large proportion of familial OC risk remains unexplained. We adopted a two‐stage design to identify new OC predisposition genes. We first carried out a large germline whole‐exome sequencing study on 158 patients from 140 families with significant OC history, but without evidence of genetic predisposition due to BRCA1/2. We then evaluated the potential candidate genes in a large case–control association study involving 381 OC cases in the Cancer Genome Atlas project and 27,173 population controls from the Exome Aggregation Consortium. Two new putative OC risk genes were identified, namely, ANKRD11, a putative tumor suppressor, and POLE, an enzyme involved in DNA repair and replication. These two genes likely confer moderate OC risk. We performed in vitro experiments and showed an ANKRD11 mutation identified in our patients markedly lowered the protein expression by compromising protein stability. Upon future validation and functional characterization, these genes may shed light on cancer etiology along with improving ascertainment power and preventive care of individuals at high risk of OC.

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Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome

Cited by 53 publications

References 25 publications

Novel Mutations and Unreported Clinical Features in KBG Syndrome

Novel Mutations and Unreported Clinical Features in KBG Syndrome

KBG syndrome involving a single-nucleotide duplication in ANKRD11

Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

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