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

Alkhateeb, Asem; Alazaizeh, Wafa

doi:10.1055/s-0038-1676649

Cited by 10 publications

(5 citation statements)

References 21 publications

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“…Clinical features are variable between patients, however, hypotonia, microcephaly, craniofacial dysmorphisms, congenital cardiac defects, gastrointestinal problems, feeding difficulties, strabismus, and sleep disturbances have been reported (Arboleda et al, 2015;Millan et al, 2016;Kennedy et al, 2019). Delayed myelination has also been observed in some patients, although was found to resolve over time (Millan et al, 2016;Alkhateeb and Alazaizeh, 2019).…”

Section: Kat6a Syndromementioning

confidence: 99%

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders

et al. 2021

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Epigenetic processes are critical for governing the complex spatiotemporal patterns of gene expression in neurodevelopment. One such mechanism is the dynamic network of post-translational histone modifications that facilitate recruitment of transcription factors or even directly alter chromatin structure to modulate gene expression. This is a tightly regulated system, and mutations affecting the function of a single histone-modifying enzyme can shift the normal epigenetic balance and cause detrimental developmental consequences. In this review, we will examine select neurodevelopmental conditions that arise from mutations in genes encoding enzymes that regulate histone methylation and acetylation. The methylation-related conditions discussed include Wiedemann-Steiner, Kabuki, and Sotos syndromes, and the acetylation-related conditions include Rubinstein-Taybi, KAT6A, genitopatellar/Say-Barber-Biesecker-Young-Simpson, and brachydactyly mental retardation syndromes. In particular, we will discuss the clinical/phenotypic and genetic basis of these conditions and the model systems that have been developed to better elucidate cellular and systemic pathological mechanisms.

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Section: Kat6a Syndromementioning

confidence: 99%

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders

et al. 2021

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“…The KAT6A Foundation (https://kat6a.org) identifies more than 330 cases; however, the true prevalence is unknown. Descriptions of KAT6A syndrome have been based primarily on medical history and case notes, due to geographically‐dispersed participants, and systematic and standardized assessments have not been used (Alkhateeb & Alazaizeh, 2019; Kennedy et al, 2019; Urreizti et al, 2020). Core features include mild to severe ID, motor delays, hypotonia, gastrointestinal issues, and cardiac malformations (Arboleda et al, 2015; Kennedy et al, 2019; Tham et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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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“…Genetic diagnosis at a younger age is important in syndromic cases because special treatments or surveillance programs are available for major symptoms. Most patients diagnosed with ARTHS have speech delays and intellectual disabilities, and early assessment of developmental delays can improve prognoses through proper treatment according to patient age [ 3 – 6 ]. In the present case, contrary to previous reports of patients with ARTHS, the genetic origin of the infant’s syndromic features was identified before an expressive language delay of mild degree developed at the age of eight months.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel KAT6A variant in an infant presenting with facial dysmorphism and developmental delay: a case report and literature review

et al. 2021

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Background Arboleda-Tham syndrome (ARTHS), caused by a pathogenic variant of KAT6A, is an autosomal dominant inherited genetic disorder characterized by various degrees of developmental delay, dysmorphic facial appearance, cardiac anomalies, and gastrointestinal problems. Case presentation A baby presented multiple facial deformities including a high arched and cleft palate, with philtral ridge and vermilion indentation, a prominent nasal bridge, a thin upper lip, low-set ears, an epicanthal fold, and cardiac malformations. Whole exome sequencing (WES) revealed a heterozygous nonsense mutation in exon 8 of the KAT6A gene (c.1312C>T, p.[Arg438*]) at 2 months of age. After a diagnosis of ARTHS, an expressive language delay was observed during serial assessments of developmental milestones. Conclusions In this study, we describe a case with a novel KAT6A variant first identified in Korea. This case broadens the scope of clinical features of ARTHS and emphasizes that WES is necessary for early diagnosis in patients with dysmorphic facial appearances, developmental delay, and other congenital abnormalities.

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

Cited by 10 publications

References 21 publications

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders

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

Identification of a novel KAT6A variant in an infant presenting with facial dysmorphism and developmental delay: a case report and literature review

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