Speech and language deficits are central to SETBP1 haploinsufficiency disorder

Abstract

Expressive communication impairment is associated with haploinsufficiency of SETBP1, as reported in small case series. Heterozygous pathogenic loss of function (LoF) variants in SETBP1 have also been identified in independent cohorts ascertained for childhood apraxia of speech (CAS), warranting further investigation of the roles of this gene in speech development. Thirty-one participants (20 males, aged 0;8 to 23;2 years, 28 with pathogenic SETBP1 LoF variants, 3 with 18q12.3 deletions) were assessed for speech, language and literacy abilities. Broader development was examined with standardised motor, social, and daily life skills assessments. Gross and fine motor deficits (94%) and intellectual impairments (68%) were common. Protracted and aberrant speech development was consistently seen, regardless of motor or intellectual ability. We expand the linguistic phenotype associated with SETBP1-LoF syndrome (SETBP1 haploinsufficiency disorder), revealing a striking presentation that implicates both motor (CAS, dysarthria) and language (phonological errors) systems, with CAS (80%) being the most common diagnosis. In contrast to past reports, the understanding of language was rarely better preserved than language expression (29%).Language was typically low, to moderately impaired, with commensurate expression and comprehension ability. Children were sociable with a strong desire to communicate. Minimally verbal children (32%) augmented speech with sign language, gestures or digital devices.Overall, relative to general development, spoken language and literacy were poorer than social, daily living, motor and adaptive behaviour skills. Our findings show that poor communication is a central feature of SETBP1 haploinsufficiency disorder, confirming this gene as a strong candidate for speech and language disorders.

SETBP1variants outside the degron disrupt DNA-binding and transcription independent of protein abundance to cause a heterogeneous neurodevelopmental disorder

“…Unlike classical SGS, individuals carrying such variants do not show major congenital or growth anomalies. Our recent systematic gene-driven studies of a large cohort with confirmed SETBP1 LoF variants revealed a far broader clinical severity spectrum than previously reported 15,16 . Despite subtle overlapping facial dysmorphisms, and in contrast to SGS, the affected individuals do not present with a recognizable facial gestalt or specific features of dysmorphisms.…”

“…Individuals with SETBP1 haploinsufficiency disorder showed significant impairments in both receptive and expressive language, suggesting SETBP1 as a strong candidate for speech and language disorders 15 . Of note, we have here demonstrated that individuals carrying SETBP1 variants outside the degron, where speech and language data were available, showed generally low language ability for all subdomains including expressive, receptive, written and social language.…”

“…Heterozygous pathogenic LoF variants in SETBP1 have been independently identified by exome/genome sequencing in different cohorts of individuals with childhood apraxia of speech (CAS) 13,17 . In a comprehensive speech phenotyping study led by Morgan et al 15 , poor communication was shown to be a central feature of SETBP1 haploinsufficiency disorder. These findings further highlight the heterogeneity and complexity of SETBP1-related aetiologies.…”

Genetic Analysis of Children With Unexplained Developmental Delay and/or Intellectual Disability by Whole-Exome Sequencing

“…Patient 12 exhibited mild ID (IQ 65–70), consistent with a recent study that ID of various levels was observed in 77% (23/30) of patients with SETBP1 haploinsufficiency disorder ( Jansen et al, 2021 ). In addition, another study indicated that aberrant speech and language development are central to SETBP1 haploinsufficiency disorder ( Morgan et al, 2021 ), and patient 12 also showed impaired speech and language development.…”

A new impact factor for European Journal of Human Genetics

“…This underscores the need for in depth phenotyping to understand the penetrance of such variants in "healthy" populations. Two studies of SETBP1 syndrome using in depth phenotyping, in this issue, provide valuable insights into this rare disease [8,9]. Helping define the associated functional strengths and weaknesses, which will help inform families.…”