Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome

Bestetti, Ilaria; Crippa, Milena; Sironi, Alessandra; Tumiatti, Francesca; Masciadri, Maura; Smeland, Marie Falkenberg; Naik, Swati; Murch, Oliver; Bonati, Maria Teresa; Spano, Alice; Cattaneo, Elisa; Mariani, Milena; Gotta, Fabio; Crosti, Francesca; Cavalli, Pietro; Pantaleoni, Chiara; Natacci, Federica; Bedeschi, Maria Francesca; Milani, Donatella; Maitz, Silvia; Selicorni, Angelo; Spaccini, Luigina; Peron, Angela; Russo, Silvia; Larizza, Lidia; Low, Karen; Finelli, Palma

doi:10.3390/ijms23115912

Cited by 7 publications

(4 citation statements)

References 37 publications

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“…In this study, we report 21 individuals with ANKRD11 (NM_013275.5) variants that are predicted to adversely impact protein function and are classified as pathogenic using the ACMG variant classification guidelines ( 22 ) ( Table 1 and Supplementary Material, Table S1 ). These are frameshift or nonsense variants located within the largest exon ( 9 ), an observed mutational hotspot in ANKRD11 . In addition, there is one individual with a splice site variant between exons 2 and 3, and two individuals with microdeletions at 16q24.3, which result in full deletion of the ANKRD11 gene.…”

Section: Resultsmentioning

confidence: 99%

“…Of those patients with missense variants and a clinical diagnosis of KBGS ( n = 13; ~5%), six individuals inherited the variant from a parent who did not meet the clinical diagnostic criteria for KBGS, and in four of those individuals, transmission is from mother to son ( 7 ). Based on published reports, a highly variable clinical presentation of inherited missense variants appears to be a hallmark of ANKRD11 ( 5 , 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…In this study, we used trio‐WES technology to detect the variant in the child and his parents, but did not find any pathogenic variants in the seven known pathological genes of CdLS. In addition, we also screened related syndromes overlapping with CdLS phenotypes, such as KBG syndrome (ANKRD11 variant‐related), CHOP syndrome (AFF4 variant‐related), and Rubinstein‐Taybi syndrome (EP300 variant‐related), but no suspected pathogenic variants in these disease‐related genes were found (Bestetti et al., 2022; Lee et al., 2022; Raible et al., 2019; Selicorni et al., 2021). Finally, we found a de novo variant, c.526C>T (p.Arg176Trp), on exon 5 of MAU2, which was located in the unknown domain between TPR‐1 and TPR‐3 of the MAU2 protein (Hinshaw et al., 2015).…”

Section: Discussionmentioning

confidence: 99%

Clinical study and genetic analysis of Cornelia de Lange syndrome caused by a novel MAU2 gene variant in a Chinese boy

Peng,

Zhu,

et al. 2023

Molec Gen & Gen Med

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BackgroundCornelia de Lange syndrome (CdLS) is mainly characterized by specific facial features, growth retardation, and bone deformities. Seven genes reportedly cause CdLS. Recent research has reported that loss‐of‐function variants affecting MAU2, which encodes a regulator of the cohesin complex, can cause CdLS. Thus far, only one MAU2‐CdLS case has been reported worldwide.MethodsWe detected a novel variant in MAU2 gene, NM_015329, c.526C>T (p.Arg176Trp) in a Chinese patient with CdLS, constructed a plasmid for in vitro transcriptional and protein level analysis, and analyzed the interaction between the MAU2/NIPBL complex using molecular dynamics (MD).ResultsThe results showed that the level of the exogenous MAU2 mutant protein was significantly reduced compared with that of the exogenous wild‐type protein. However, MD analysis predicted an increased binding free energy between the MAU2 and NIPBL proteins that may impact the structural stability of the complex.ConclusionWe investigated a MAU2‐CdLS case in a Chinese family, which strengthens the association between MAU2 variants and CdLS phenotypes. We therefore propose that MAU2 be included in the CdLS gene screening list.

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“…He presented with some features of CdLS including anteverted nares, short stature, global developmental delay, microcephaly, small hands and short 5th finger (Table 1; scored 7). He also presented with macrodontia of the upper central incisors, which is a component of KBGS (25). Although KBG has clinical features overlapping with CdLS, the average clinical score is lower than the NIPBL cohort.…”

Section: Discussionmentioning

confidence: 99%

Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review

Shangguan

Chen

2022

Front. Pediatr.

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BackgroundCornelia de Lange syndrome (CdLS) is a genetic disorder caused by variants in cohesion genes including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. According to the 2018 consensus statement, a patient with clinical scored ≥ 11 points could be diagnosed as CdLS. However, some variants in non-cohesion genes rather than cohesion genes can manifest as phenotypes of CdLS.ObjectivesThis study describes six variants of non-cohesion genes (KDM6A, KMT2D, KMT2A ANKRD11, and UBE2A), and assesses the reliability of 11-points scale criteria in the clinical diagnosis of CdLS.MethodsWhole-exome sequencing (WES) was performed on six patients with features of CdLS. Phenotypic and genotypic spectra of 40 previously reported patients with features of CdLS caused by non-cohesion genes variants and 34 previously reported patients with NIPBL variants were summarized. Clinical score comparison among patients with NIPBL variants versus those with variants in non-cohesin genes was performed.ResultsVariants in non-cohesion genes were found in six patients [KMT2A (n = 2), KMT2D, ANKRD11, KDM6A, and UBE2A]. Of them, four variants (KMT2A c.7789C > T, ANKRD11 c.1757_1776del, KDM6A c.655-1G > A, and UBE2A c.439C > T) were novel. Combining with previously reported cases, 46 patients with phenotypes of CdLS caused by variants in 20 non-cohesion genes are now reported. From this total cohort, the average clinical score of patients in ANKRD11 cohort, SETD5 cohort, and AFF4 cohort was statistically lower than those in NIPBL cohort (8.92 ± 1.77 vs. 12.23 ± 2.58, 7.33 ± 2.52 vs. 12.23 ± 2.58, 5.33 ± 1.53 vs. 12.23 ± 2.58; p < 0.05). The average clinical score of KMT2A cohort, EP300 cohort, and NIPBL cohort had not significantly different from (11 ± 2.19 vs. 12.23 ± 2.58, 10 ± 4.58 vs. 12.23 ± 2.58; p > 0.05).ConclusionWe described 4 novel variants of non-cohesion genes in six Chinese patients with phenotypes of CdLS. Of note, three genes (KMT2D, KDM6A, and UBE2A) causing features of CdLS have never been reported. The proposed clinical criteria for CdLS needed to be updated and refined, insofar as WES was necessary to confirm the diagnosis of CdLS. Our study expanded the spectra of non-cohesion genetic variations in patients with features of CdLS.

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Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome

Cited by 7 publications

References 37 publications

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

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

Clinical study and genetic analysis of Cornelia de Lange syndrome caused by a novel MAU2 gene variant in a Chinese boy

Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review

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