Lin‐Gettig syndrome: Craniosynostosis expands the spectrum of the <i>KAT6B</i> related disorders

Bashir, Rani A.; Dixit, Abhijit; Goedhart, Caitlin; Innes, A. Micheil; Ferreira, Patrick; Hasan, Shabih U.; Au, Ping Yee Billie

doi:10.1002/ajmg.a.38355

Cited by 13 publications

(20 citation statements)

References 26 publications

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“…The most common mechanism is presumed to be haploinsufficiency, as a majority of the individuals have a loss-of-function variant [32]; this concords with our results (Tables 2 and 4). A few of the chromatinopathies have previously been associated with CS: Kabuki syndrome, Bohring-Opitz syndrome (BOS), and two cases of KAT6B-related disorders [31][32][33][34][35][36]. To our knowledge, only one case of CS in CHARGE syndrome [37], one case in Floating-Harbor syndrome [38], one case in 2q37 deletion syndrome [30], and none in Kleefstra syndrome have been reported.…”

Section: Discussionmentioning

confidence: 99%

Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis

et al. 2020

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An accurate diagnosis of syndromic craniosynostosis (CS) is important for personalized treatment, surveillance, and genetic counselling. We describe detailed clinical criteria for syndromic CS and the distribution of genetic diagnoses within the cohort. The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve individuals with syndromic CS born between 1 January 2002 and 30 June 2019. All individuals were assessed by a clinical geneticist and classified using defined clinical criteria. A stepwise approach consisting of single-gene analysis, comparative genomic hybridization (aCGH), and exome-based high-throughput sequencing, first filtering for 72 genes associated with syndromic CS, followed by an extended trio-based panel of 1570 genes were offered to all syndromic CS cases. A total of 381 individuals were registered with CS, of whom 104 (27%) were clinically classified as syndromic CS. Using the single-gene analysis, aCGH, and custom-designed panel, a genetic diagnosis was confirmed in 73% of the individuals (n = 94). The diagnostic yield increased to 84% after adding the results from the extended trio-based panel. Common causes of syndromic CS were found in 53 individuals (56%), whereas 26 (28%) had other genetic syndromes, including 17 individuals with syndromes not commonly associated with CS. Only 15 individuals (16%) had negative genetic analyses. Using the defined combination of clinical criteria, we detected among the highest numbers of syndromic CS cases reported, confirmed by a high genetic diagnostic yield of 84%. The observed genetic heterogeneity encourages a broad genetic approach in diagnosing syndromic CS.

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Section: Discussionmentioning

confidence: 99%

Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis

et al. 2020

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“…Recently, 2 patients with sagittal craniosynostosis and clinical manifestations consistent with the Lin-Gettig syndrome phenotype have been described as carriers of de novo frameshift mutations in KAT6B . Interestingly, both patients had features overlapping those of SBBYSS and GTPTS (Bashir et al, 2017 ), suggesting that Lin-Gettig syndrome is in the spectrum of KAT6B -related disorders as well.…”

Section: Syndromic Craniosynostosis As a Nonspecific Feature Of Condimentioning

confidence: 97%

Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples

et al. 2017

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Craniosynostosis is a heterogeneous condition caused by the premature fusion of cranial sutures, occurring mostly as an isolated anomaly. Pathogenesis of non-syndromic forms of craniosynostosis is largely unknown. In about 15–30% of cases craniosynostosis occurs in association with other physical anomalies and it is referred to as syndromic craniosynostosis. Syndromic forms of craniosynostosis arise from mutations in genes belonging to the Fibroblast Growth Factor Receptor (FGFR) family and the interconnected molecular pathways in most cases. However it can occur in association with other gene variants and with a variety of chromosome abnormalities as well, usually in association with intellectual disability (ID) and additional physical anomalies. Evaluating the molecular properties of the genes undergoing intragenic mutations or copy number variations (CNVs) along with prevalence of craniosynostosis in different conditions and animal models if available, we made an attempt to define two distinct groups of unusual syndromic craniosynostosis, which can reflect direct effects of emerging new candidate genes with roles in suture homeostasis or a non-specific phenotypic manifestation of pleiotropic genes, respectively. RASopathies and 9p23p22.3 deletions are reviewed as examples of conditions in the first group. In particular, we found that craniosynostosis is a relatively common component manifestation of cardio-facio-cutaneous (CFC) syndrome. Chromatinopathies and neurocristopathies are presented as examples of conditions in the second group. We observed that craniosynostosis is uncommon on average in these conditions. It was randomly associated with Kabuki, Koolen-de Vries/KANSL1 haploinsufficiency and Mowat–Wilson syndromes and in KAT6B-related disorders. As an exception, trigonocephaly in Bohring-Opitz syndrome reflects specific molecular properties of the chromatin modifier ASXL1 gene. Surveillance for craniosynostosis in syndromic forms of intellectual disability, as well as ascertainment of genomic CNVs by array-CGH in apparently non-syndromic craniosynostosis is recommended, to allow for improvement of both the clinical outcome of patients and the accurate individual diagnosis.

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“…Two male patients with sagittal suture synostosis and a phenotype of Lin-Gettig syndrome had de novo frameshift mutations in KAT6B [Bashir et al, 2017]. The patients had hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia [Bashir et al, 2017].…”

Section: Kat6bmentioning

confidence: 99%

“…The patients had hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia [Bashir et al, 2017].…”

Section: Kat6bmentioning

confidence: 99%

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Genetic Causes of Craniosynostosis: An Update

Goos

Mathijssen²

2018

Mol Syndromol

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In 1993, Jabs et al. were the first to describe a genetic origin of craniosynostosis. Since this discovery, the genetic causes of the most common syndromes have been described. In 2015, a total of 57 human genes were reported for which there had been evidence that mutations were causally related to craniosynostosis. Facilitated by rapid technological developments, many others have been identified since then. Reviewing the literature, we characterize the most common craniosynostosis syndromes followed by a description of the novel causes that were identified between January 2015 and December 2017.

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Lin‐Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders

Cited by 13 publications

References 26 publications

Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis

Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis

Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples

Genetic Causes of Craniosynostosis: An Update

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