KAT6A Syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants

Kennedy, Joanna; Goudie, David; Blair, Edward; Chandler, Kate; Joss, Shelagh; McKay, Victoria; Green, Andrew J.; Armstrong, Ruth; Lees, Melissa; Kamien, Benjamin; Hopper, Bruce; Tan, Tiong Yang; Yap, Patrick; Stark, Zornitza; Okamoto, Nobuhiko; Miyake, Noriko; Matsumoto, Naomichi; Macnamara, Ellen; Murphy, Jennifer L.; McCormick, Elizabeth; Hákonarson, Hákon; Falk, Marni J.; Dong, Le; Blackburn, Patrick R.; Klee, Eric W.; Babovic‐Vuksanovic, Dusica; Schelley, Susan; Hudgins, Louanne; Kant, Sarina G.; Isidor, Bertrand; Cogné, Benjamin; Bradbury, Kimberley; Williams, Mark; Patel, Chirag; Heussler, Helen; Duff‐Farrier, Celia; Lakeman, Phillis; Scurr, Ingrid; Kini, Usha; Elting, Mariet W.; Reijnders, Margot R.F.; Schuurs-Hoeijmakers, Janneke; Wafik, Mohamed; Blomhoff, Anne; Ruivenkamp, Claudia; Nibbeling, Esther; Dingemans, Alexander J.M.; Douine, Emilie D.; Nelson, Stanley F.; Arboleda, Valerie A.; Newbury‐Ecob, Ruth

doi:10.1038/s41436-018-0259-2

Cited by 82 publications

(168 citation statements)

References 35 publications

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“…KAT6A or KAT6B variants have been identified in ~300 individuals with neurodevelopmental disorders characteristic of intellectual disability (24)(25)(26)(27)(28)(29)(30)(31)(32). BRPF1 variants are present in 40 cases of syndromic intellectual disability ( Figs.…”

Section: Discussionmentioning

confidence: 99%

“…S8, A and C). A few KAT6A or KAT6B variants alter their MYST domains (31,32) and may thus affect acylation. The drugs valproate and vorinostat rescued acylation defects in cultured cells with mouse Brpf1 (or human BRPF1) mutations (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, their regulatory mechanisms may be different in vivo. Their knockout mice display distinct phenotypes (23), and patients with KAT6A or KAT6B variants exhibit different clinical features (24)(25)(26)(27)(28)(29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

“…3A and 4A) (12,33), most of the KAT6A and KAT6B variants associated with syndromic intellectual disability delete the C-terminal part but leave the MYST domain intact (fig. S8, A and C) (24)(25)(26)(27)(28)(29)(30)(31). Nonsense-mediated mRNA decay does not appear to affect transcripts with truncating mutations because most of them are located within the last large coding exon (24)(25)(26)(27)(28)(29)(30), so many KAT6A or KAT6B variants are not expected to alter H3K23 acetylation and propionylation.…”

Section: Developmental Disorder-associated Brpf1 Mutations Diminish Hmentioning

confidence: 99%

“…In 2012 and 2015, they were reported to be mutated in individuals with intellectual disability and neurodevelopmental disorders (24)(25)(26)(27)(28)(29)(30). A recent study analyzed 76 individuals with KAT6A variants (31), and at least 210 persons with these variants have enrolled in the KAT6A Foundation. Known cases with KAT6B variants have also exceeded 60 (32).…”

Section: Introductionmentioning

confidence: 99%

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Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

et al. 2020

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Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Developmental Disorder-associated Brpf1 Mutations Diminish Hmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

et al. 2020

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BRPF1‐associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development

Souza

Valle²,

Santos³

et al. 2022

American J of Med Genetics Pt A

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In 2017, Mattiolli et al. and Yan et al. described a series of patients with clinical findings essentially characterized by intellectual disabilities, ptosis, hypotonia, epilepsy, and weakness. They also found in these patients distinct heterozygous mutations in the BRPF1 gene, which plays a role in epigenetic regulation by promoting histone acetylation. The disease is known as Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP, OMIM #617333). Later, another 20 patients were also described by distinct reports, suggesting IDDDFP could be a more frequent cause of intellectual disability as it was thought before. Here, we describe a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination.The patient has a rare nonsense variant on exon 3 of BRPF1 gene. We also describe a phenotypic amplification for conditions related to deficiency in histone modifications.

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Speech and language development and genotype–phenotype correlation in 49 individuals with KAT6A syndrome

John

Amor

Morgan

2022

American J of Med Genetics Pt A

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Pathogenic KAT6A variants cause syndromic neurodevelopmental disability. “Speech delay” is reported, yet none have examined specific speech and language features of KAT6A syndrome. Here we phenotype the communication profile of individuals with pathogenic KAT6A variants. Medical and communication data were acquired via standardized surveys and telehealth‐assessment. Forty‐nine individuals (25 females; aged 1;5–31;10) were recruited, most with truncating variants (44/49). Intellectual disability/developmental delay (42/45) was common, mostly moderate/severe, alongside concerns about vision (37/48), gastrointestinal function (33/48), and sleep (31/48). One‐third (10/31) had a diagnosis of autism. Seventy‐three percent (36/49) were minimally‐verbal, relying on nonverbal behaviors to communicate. Verbal participants (13/49) displayed complex and co‐occurring speech diagnoses regarding the perception/production of speech sounds, including phonological impairment (i.e., linguistic deficits) and speech apraxia (i.e., motor planning/programming deficits), which significantly impacted intelligibility. Receptive/expressive language and adaptive functioning were also severely impaired. Truncating variants in the last two exons of KAT6A were associated with poorer communication, daily‐living skills, and socialization outcomes. In conclusion, severe communication difficulties are present in KAT6A syndrome, typically on a background of significant intellectual disability, vision, feeding and motor deficits, and autism in some. Most are minimally‐verbal, with apparent contributions from underlying motor deficits and cognitive‐linguistic impairment. Alternative/augmentative communication (AAC) approaches are required for many into adult life. Tailored AAC options should be fostered early, to accommodate the best communication outcomes.

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KAT6A Syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants

Cited by 82 publications

References 35 publications

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

BRPF1‐associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development

Speech and language development and genotype–phenotype correlation in 49 individuals with KAT6A syndrome

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