Clinical and molecular findings in 39 patients with KBG syndrome caused by deletion or mutation of <i>ANKRD11</i>

Goldenberg, Alice; Riccardi, Florence; Tessier, Aude; Pfundt, Rolph; Busa, Tiffany; Cacciagli, Pierre; Capri, Yline; Coutton, Charles; Delahaye‐Duriez, Andrée; Frébourg, Thierry; Gatinois, Vincent; Guerrot, Anne‐Marie; Geneviève, David; Lecoquierre, François; Jacquette, Aurélia; Kien, Philippe Khau Van; Leheup, Bruno; Marlin, Sandrine; Verloès, Alain; Michaud, Vincent; Nadeau, Gwenaël; Mignot, Cyril; Parent, Philippe; Rossi, Massimiliano; Toutain, Annick; Schaefer, Eric; Thauvin‐Robinet, Christel; Maldergem, Lionel Van; Thévenon, Julien; Satre, Véronique; Perrin, Laurence; Vincent‐Delorme, Catherine; Sorlin, Arthur; Missirian, Chantal; Villard, Laurent; Mancini, Julien; Saugier-Veber, Pascale; Philip, Nicole

doi:10.1002/ajmg.a.37878

Cited by 74 publications

(166 citation statements)

References 39 publications

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“…Additionally, this case also demonstrates the variability of the clinical manifestations of KBG syndrome, as any macrodontia in the proband was not noticeable enough to be recognized and associated with any syndrome diagnosis by any clinician, including medical geneticists, before the molecular diagnosis of the syndrome. This is consistent with the very recent suggestion that macrodontia should not be considered a “mandatory feature” of KBG syndrome (Goldenberg et al 2016). In addition, seizures are an often reported feature of KBG syndrome, found in up to 28% of patients (Skjei et al 2007).…”

Section: Discussionsupporting

confidence: 92%

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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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Section: Discussionsupporting

confidence: 92%

“…More than 100 cases have now been reported (see Fig. 6; Ockeloen et al 2015; Goldenberg et al 2016); however, it is likely that KBG syndrome is underdiagnosed because dysmorphic features may be underreported, subtle, or even nonexistent, and cognitive delay can vary from mild to moderate (Crippa et al 2015). …”

Section: Discussionmentioning

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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“…Two patients showed hematological abnormalities (one had a pancytopenia with bone marrow hypoplasia and the second had anemia and leukopenia). Only 1 patient was previously reported with acute myeloid leukemia [Goldenberg et al, 2016], and a role of ANKRD11 in cancer predisposition was proposed, but not confirmed [Neilsen et al, 2008;Lim et al, 2012]. The presence of thrombocytopenia was pointed out as a possible feature distinguishing between KBG syndrome and 16q24 microdeletion syndrome, where ANKRD11 flanking genes are also involved [Novara et al, 2017].…”

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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“…The following patients have been previously reported in articles: #3 and #4, #8, #13, #14, #23, #26, and #51 …”

Section: Methodsmentioning

confidence: 99%

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients

et al. 2017

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Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.

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Clinical and molecular findings in 39 patients with KBG syndrome caused by deletion or mutation of ANKRD11

Cited by 74 publications

References 39 publications

KBG syndrome involving a single-nucleotide duplication in ANKRD11

KBG syndrome involving a single-nucleotide duplication in ANKRD11

Novel Mutations and Unreported Clinical Features in KBG Syndrome

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients

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