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

Abstract

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.

Diagnosis of Arboleda‐Tham syndrome by whole‐exome sequencing in an Asian girl with severe developmental delay

“…Arboleda‐Tham syndrome (ARTHS, OMIM# 616268) is an autosomal dominant inherited genetic disorder characterized by dysmorphic facial appearance, mild to severe developmental delay with speech delay, gastrointestinal problems and cardiac anomalies (Bae et al, 2021 ). The main phenotype of the Arboleda‐Tham syndrome are developmental delay with speech delay, facial dysmorphism, hypotonia, renal/urogenital problems, epilepsy, behavioral problems, hearing loss, and cardiac defects (Kennedy et al, 2019 ; St John et al, 2022 ). Overall, more and more patients with KAT6A variants with different clinical presentations have been reported (Arboleda et al, 2015 ; Bae et al, 2021 ; Elenius et al, 2017 ; Kennedy et al, 2019 ; Lin et al, 2020 ; Millan et al, 2016 ; Satoh et al, 2017 ; St John et al, 2022 ; Tham et al, 2015 ; Zwaveling‐Soonawala et al, 2017 ).…”

“…These patients presented with a spectrum of phenotypes including intellectual disability, speech delay, neonatal hypotonia, early feeding difficulties, and delayed motor skills. Simultaneously, they also had subtle facial manifestations including microretrognathia, thin upper lip, broad nasal tip, bi‐temporal narrowing, and low‐set/posteriorly rotated ears (St John et al, 2022 ; Tham et al, 2015 ). Additional clinical features of KAT6A syndrome also noted among the patient included sleep disturbances and behavioral abnormalities (Ai et al, 2023 ).…”

Epigenetics of cognition and behavior: insights from Mendelian disorders of epigenetic machinery

“…In contrast, those with KAT6A syndrome uniformly show intellectual disability and developmental delay—with receptive/expressive language and communication deficits as the most well-documented feature [ 67 ]. Nearly 70% of affected individuals are minimally verbal [ 68 ]. Comprehension skills are reported to be more preserved than expressive language [ 67 ].…”

“…Comprehension skills are reported to be more preserved than expressive language [ 67 ]. To date, with the exception of St. John et al [ 68 ], descriptions of the syndrome have largely relied on retrospective review of medical history or case studies, and thus most non-verbal cognitive functions (e.g., non-verbal reasoning, spatial processing, executive functions, etc.) remains poorly characterized.…”

“…remains poorly characterized. Studies have documented 25–33% of those with KAT6A syndrome have a diagnosis of autism spectrum disorder although the rates may vary based on diagnostic methods applied [ 68 ]. Emotional disturbances appear to be less of a concern among affected individuals [ 69 ].…”