Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

Boer, Elke de; Ockeloen, Charlotte W.; Kampen, Rosalie A.; Hampstead, Juliet E.; Dingemans, Alexander J.M.; Rots, Dmitrijs; Lutje, Lukas; Ashraf, Tazeen; Baker, Richard; Barat‐Houari, Mouna; Angle, Brad; Chatron, Nicolas; Wieczorek, Dagmar; Devinsky, Orrin; Dubourg, Christèle; Elmslie, Frances; Elloumi, Houda Zghal; Faivre, Laurence; Fitzgerald-Butt, Sarah; Geneviève, David; Goos, Jacqueline A.C.; Helm, Benjamin M.; Kini, Usha; Lasa-Aranzasti, Amaia; Lesca, Gaëtan; Lynch, Sally Ann; Mathijssen, Irene M.J.; McGowan, Ruth; Monaghan, Kristin G.; Odent, Sylvie; Pfundt, Rolph; Putoux, Audrey; Reeuwijk, Jeroen van; Santen, Gijs W.E.; Sasaki, Erina; Sorlin, Arthur; Spek, Peter J. van der; Stegmann, Alexander P.A.; Swagemakers, Sigrid; Valenzuela, Irene; Viora‐Dupont, Eléonore; Vitobello, Antonio; Ware, Stephanie M.; Wéber, Mathys; Gilissen, Christian; Low, Karen; Fisher, Simon E.; Vissers, Lisenka E.L.M.; Wong, Maggie M. K.; Kleefstra, Tjitske

doi:10.1016/j.gim.2022.06.007

Cited by 19 publications

(12 citation statements)

References 37 publications

(70 reference statements)

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“…Moreover, molecular analysis of cohorts of patients with KBG syndrome have found that the majority of ANKRD11 pathogenic variants are frameshift and nonsense variants leading to a loss‐of‐function, and presumably, haploinsufficiency as well (Gnazzo et al, 2020; Goldenberg et al, 2016; Loberti et al, 2022; Low et al, 2016; Parenti et al, 2021; Scarano et al, 2019). Recenty, functional studies performed on ANKRD11 missense variants found these decreased ANKRD11 stability and transcriptional activity, further supporting haploinsufficiency as a pathologic mechanism for KBG syndrome (de Boer et al, 2022).…”

Section: Discussionmentioning

confidence: 84%

Deletion of first noncoding exon in ANKRD11 leads to KBG syndrome

Borja

Zafeer

Rodriguez

et al. 2023

American J of Med Genetics Pt A

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Phenotypic features of KBG syndrome include craniofacial anomalies, short stature, cognitive disability and behavioral findings. The syndrome is caused by heterozygous pathogenic single nucleotide variants and indels in ANKRD11, or a heterozygous deletion of 16q24.3 that includes ANKRD11. We performed genome sequencing on a patient with clinical manifestations of KBG syndrome including distinct craniofacial features as well as a history of mild intellectual disability and attention‐deficit hyperactivity disorder. This led to the identification of a 43 kb intragenic deletion of ANKRD11 affecting the first noncoding exon while leaving the coding regions intact. Review of the literature shows that this is the smallest 5′ deletion affecting only the noncoding exons of ANKRD11. Real‐time polymerase chain reaction demonstrated that the copy number variant was not present in either of the proband's parents, suggesting it occurred de novo. RNA expression analysis demonstrated significantly decreased transcript abundance compared to controls. This provides new evidence for haploinsufficiency as a mechanism of disease in KBG syndrome.

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Section: Discussionmentioning

confidence: 84%

Deletion of first noncoding exon in ANKRD11 leads to KBG syndrome

Borja

Zafeer

Rodriguez

et al. 2023

American J of Med Genetics Pt A

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“…This type of variable intrafamilial expression of KBGS has been reported in multiple families in which an ANKRD11 missense variant is vertically transmitted ( 5 , 7–9 ). Another report investigating de novo missense variants within ANKRD11 ’s repression domain 2 concluded that the phenotype of individuals with these variants was in line with KBGS ( 28 ). The report also confirmed these variants have a loss-of-function effect on the ANKRD11 protein.…”

Section: Discussionmentioning

confidence: 99%

“…The report also confirmed these variants have a loss-of-function effect on the ANKRD11 protein. While the transcript can escape NMD, the protein is unstable and unable to carry out trans-repression activities ( 28 ). That is, missense variants in ANKRD11 have a variable impact on the protein expression and function, which may contribute to the variable phenotype observed.…”

Section: Discussionmentioning

confidence: 99%

ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome

Awamleh

Choufani

Cytrynbaum

et al. 2022

Human Molecular Genetics

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Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood termed DNAm signatures. Given ANKRD11’s role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3, and 28 typically developing individuals, using Illumina’s Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with KBGS and pathogenic variants in ANKRD11 (n = 14) from typically developing controls (n = 28) and was also validated in seven additional individuals with pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of 4 individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show the DNAm profile of two individuals with 16q24.3 microdeletions, was indistinguishable from the DNAm profile of individuals with pathogenic variants in ANKRD11 and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11.

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“…What is known is that at least some mutations in ANKRD11 lead to ANKRD11 protein instability, as well as altered transcriptional activity and epigenetic signature. [6][7][8][9] As with all diseases, the intersection of genetics, epigenetics, and environmental factors is critical in determining etiology. 10 In the case of a rare disorder such as KBG syndrome, little is known about the combination of factors that produce it or whether any genetic and environmental insults can manifest as early as during pregnancy.…”

Section: Introductionmentioning

confidence: 99%

Documentation and prevalence of prenatal and neonatal outcomes in a cohort of individuals with KBG syndrome

Kierzkowska

Sarino

Carter

et al. 2023

Preprint

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Mutations in the Ankyrin Repeat Domain 11 (ANKRD11) gene are associated with KBG syndrome, a developmental disability that affects multiple organ systems and presents with a variety of skeletal, cardiac, gastrointestinal, and neuropsychiatric manifestations. The function of ANKRD11 in human growth and development is not well understood, but its importance is established by the fact that total gene knockout is lethal in mice embryos and by its role in chromatin regulation, transcription, and development. Individuals with KBG syndrome are often misdiagnosed or undiagnosed until later in life, due to a combination of varying phenotypes, lack of targeted prenatal screening, and lack of documentation of prenatal and neonatal symptoms. The present study aims to report perinatal outcomes in individuals with KBG syndrome and their families and compare them to the prevalence in the overall population. We obtained data from 42 individuals through videoconferences, notes, and emails. Our results show that 45.2% of our cohort was born by C-section, 33.3% had a congenital heart defect, 23.8% were born before 37-weeks' gestation, 23.8% were admitted to the NICU, 14.3% were small for gestational age, and 14.3% of the families in our cohort had a history of miscarriage. The prevalence of birth by C-section, premature birth, NICU admission, and small for gestational age was higher in our cohort compared to the overall population, including non-Hispanic and Hispanic populations. Other reports included feeding difficulties (21.4%), neonatal jaundice (14.3%), decreased fetal movement (7.14%), and pleural effusions in utero (4.67%). These findings suggest that there may be an association between ANKRD11 mutations and perinatal complications, and further research is needed to better assess the mechanisms behind this relationship. Comprehensive perinatal studies about KBG syndrome and updated documentation of its phenotypes can facilitate earlier detection, diagnosis, and treatment.

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Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

Cited by 19 publications

References 37 publications

Deletion of first noncoding exon in ANKRD11 leads to KBG syndrome

Deletion of first noncoding exon in ANKRD11 leads to KBG syndrome

ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome

Documentation and prevalence of prenatal and neonatal outcomes in a cohort of individuals with KBG syndrome

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