Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome

Crippa, Milena; Rusconi, Daniela; Castronovo, Chiara; Bestetti, Ilaria; Russo, Silvia; Cereda, Anna; Selicorni, Angelo; Larizza, Lidia; Finelli, Palma

doi:10.1186/s13039-015-0126-7

Cited by 19 publications

(32 citation statements)

References 18 publications

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“…almost 200 individuals have been reported in the medical literature, but it is likely that KBG syndrome is underdiagnosed because many of its features, including ID, are often mild, and none of the features are a prerequisite for the diagnosis [Sirmaci et al, 2011;Crippa et al, 2015].…”

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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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mentioning

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%

“…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%

“…There are two functional domains that act as transcriptional repressors and one domain that functions as a transcriptional promoter (Zhang et al 2007). The majority of reported mutations in KBG syndrome result in a truncated protein that affects a domain for transcriptional repression (Crippa et al 2015). ANKRD11 interacts with the p160 coactivator and the nuclear receptor complex, and it functions to inhibit ligand-dependent transcriptional activation by recruiting histone deacytelases (HDACs) (Sirmaci et al 2011).…”

Section: Discussionmentioning

confidence: 99%

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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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“…Height SDS of 72 patients with ANKRD11 aberration (Crippa et al, ; Goldenberg et al, ; Isrie et al, ; Li et al, ; Novara et al, ; Ockeloen et al, ; Reynaert et al, ; Sirmaci et al, ; Walz et al, ; Xu et al, ). The height of 42 patients below −2.0 SD account for 58% of 72 total.…”

Section: Discussionmentioning

confidence: 99%

A heterozygous point mutation of the ANKRD11 (c.2579C>T) in a Chinese patient with idiopathic short stature

Kang

et al. 2019

Molec Gen & Gen Med

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BackgroundPathogenic variants of ANKRD11 have been reported to cause KBG syndrome characterized by short stature, characteristic facial appearance, intellectual disability, macrodontia, and skeletal anomalies. However, the direct clinical relevance of ANKRD11 mutation with short stature is yet unknown.MethodsHere, we report a Chinese boy with idiopathic short stature (ISS) based on clinical and genetic characteristics. Comprehensive medical evaluations were performed including metabolic studies, endocrine function tests, bone X‐rays, and echocardiography. Whole‐exome and Sanger sequencing was used to detect and confirm genetic mutations associated with short stature in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools and repositories of sequence variation. Twenty‐four months follow‐up was performed to observe the growth rate of the patient treated with recombinant human growth hormone (GH).ResultsOne heterozygous point mutation (c.2579C>T) was confirmed in the ANKRD11 gene of the patient and inherited from his mother. This mutation site was located within the highly conservative region of ANKRD11 protein and predicted to be possibly damaging in several in silico prediction programs and repositories of sequence variation. Additionally, patient underwent GH replacement therapy for 24 months exhibited good response to the treatment.ConclusionA heterozygous point mutation of AKNRD11 gene was identified in a Chinese patient with short stature phenotype. The patient was treated effectively with GH supplementation.

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Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome

Cited by 19 publications

References 18 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

A heterozygous point mutation of the ANKRD11 (c.2579C>T) in a Chinese patient with idiopathic short stature

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