Variants in <i>KAT6A</i> and pituitary anomalies

Zwaveling-Soonawala, Nitash; Maas, Saskia M.; Alders, Mariëlle; Majoie, Charles B. L. M.; Fliers, Eric; Trotsenburg, A S Paul van; Hennekam, Raoul C. M.

doi:10.1002/ajmg.a.38330

Cited by 13 publications

(10 citation statements)

References 7 publications

(9 reference statements)

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“…Cardiac defects have been reported in around 70% of patients bearing late truncating mutations, but not hitherto in patients with missense mutations. Brain abnormalities, found in three of our patients (Patients 2, 3 and 5), have been frequently reported, including delayed myelination [13] and benign enlargement of the pericerebral areas [9], with the lack of the olfactory bulb [6] and pituitary abnormalities [11] being the two most consistent and noteworthy midline neuroimaging findings.…”

Section: Discussionsupporting

confidence: 66%

“…Since 2015, around 80 cases of syndromic intellectual disability due to mutations at the KAT6A gene have been described in the literature, delineating a new syndrome with variable presentation ( Table 2 and Fig. 3) [4][5][6][7][8][9][10][11][12][13][14][15]. Here, we present 5 patients with de novo variants at KAT6A, four 'late truncating' and one missense variant, and we describe their clinical presentations, adding further clinical and molecular delineation to the KAT6A syndrome.…”

Section: Discussionmentioning

confidence: 96%

“…32; MIM # 616268). To date, a total of 79 patients have been reported [4][5][6][7][8][9][10][11][12][13][14][15]. All of them present with developmental delay (DD) or intellectual disability (ID) with speech delay.…”

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confidence: 99%

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Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

Urreizti

López-Martín

Martinez‐Monseny

et al. 2020

Orphanet J Rare Dis

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Background: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement.Results: In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient's lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation.Conclusions: An extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 96%

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Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

Urreizti

López-Martín

Martinez‐Monseny

et al. 2020

Orphanet J Rare Dis

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“…9 However, the full spectrum of clinical manifestation of the autosomal dominant disease KAT6A syndrome, of which 76 patients have been previously described to date, has highly variable penetrance. 2,9,10,[12][13][14][15][16][17] These individual cases of KAT6A syndrome had gone previously unrecognized and discovered only after WES. In the setting of high genetic heterogeneity and gaps in knowledge pertaining to the genetic etiology of many causes of ID, WES has become a powerful instrument in the investigation of de novo pathogenic variants as a common cause of neurodevelopmental disorders.…”

Section: Discussionmentioning

confidence: 99%

A Novel Frameshift Mutation in KAT6A Is Associated with Pancraniosynostosis

et al. 2020

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De novo heterozygous mutations in the KAT6A gene give rise to a distinct intellectual disability syndrome, with features including speech delay, cardiac anomalies, craniofacial dysmorphisms, and craniosynostosis. Here, we reported a 16-year-old girl with a novel pathogenic variant of the KAT6A gene. She is the first case to possess pancraniosynostosis, a rare suture fusion pattern, affecting all her major cranial sutures. The diagnosis of KAT6A syndrome is established via recognition of its inherent phenotypic features and the utilization of whole exome sequencing. Thorough craniofacial evaluation is imperative, craniosynostosis may require operative intervention, the delay of which may be detrimental.

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“…Furthermore, many patients with KAT6A mutations underwent MRI but major brain abnormalities are rare. Mild abnormalities such as thin corpus callosum or delayed myelination have been reported, 4,15,16 most of which resolved over time. In our patient, the second MRI showed improved features, consistent with previous reports.…”

Section: Discussionmentioning

confidence: 99%

A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

Alkhateeb

Alazaizeh

2018

J Pediatr Genet

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Intellectual disability is a common condition with multiple etiologies. The number of monogenic causes has increased steadily in recent years due to the implementation of next generation sequencing. Here, we describe a 2-year-old boy with global developmental delay and intellectual disability. The child had feeding difficulties since birth. He had delayed motor skills and muscular hypotonia. Brain magnetic resonance imaging revealed diffuse white matter loss and thinning of the corpus callosum. Banded karyotype and comparative genomic hybridization (CGH) array were normal. Whole exome sequencing revealed a novel de novo frameshift mutation c.3390delA (p.Lys1130Asnfs*4) in KAT6A gene (NM_006766.4). The heterozygous mutation was confirmed by Sanger sequencing in the patient and its absence in his parents. KAT6A that encodes a histone acetyltransferase has been recently found to be associated with a neurodevelopmental disorder autosomal dominant mental retardation 32 (OMIM: no. 616268). Features of this disorder are nonspecific, which makes it difficult to characterize the condition based on the clinical symptoms alone. Therefore, our findings confirm the utility of whole exome sequencing to quickly and reliably identify the etiology of such conditions.

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Variants in KAT6A and pituitary anomalies

Cited by 13 publications

References 7 publications

Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

A Novel Frameshift Mutation in KAT6A Is Associated with Pancraniosynostosis

A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

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