Clinical delineation of SETBP1 haploinsufficiency disorder

Jansen, Nadieh A; Braden, Ruth; Srivastava, Siddharth; Otness, Erin F; Lesca, Gaëtan; Rossi, Massimiliano; Nizon, Mathilde; Bernier, Raphael; Quēlin, Chloé; Haeringen, Arie van; Kleefstra, Tjitske; Wong, Maggie M. K.; Whalen, Sandra; Fisher, Simon E.; Morgan, Angela; Bon, Bregje W.M. van

doi:10.1038/s41431-021-00888-9

Cited by 16 publications

(14 citation statements)

References 20 publications

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“…De novo gain-of-function variants of SETBP1 are associated with Schinzel-Giedion midface retraction syndrome (MIM #269150), while haploinsufficiency of SETBP1 caused by loss-of-function (LoF) variant or a heterozygous gene deletion is related to DD, autosomal dominant 29 (MIM #616078). 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.…”

Section: Discussionsupporting

confidence: 88%

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

et al. 2021

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Background: Whole-exome sequencing (WES) has been recommended as a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders (NDDs). We aimed to identify the genetic causes of 17 children with developmental delay (DD) and/or intellectual disability (ID).Methods: WES and exome-based copy number variation (CNV) analysis were performed for 17 patients with unexplained DD/ID.Results: Single-nucleotide variant (SNV)/small insertion or deletion (Indel) analysis and exome-based CNV calling yielded an overall diagnostic rate of 58.8% (10/17), of which diagnostic SNVs/Indels accounted for 41.2% (7/17) and diagnostic CNVs accounted for 17.6% (3/17).Conclusion: Our findings expand the known mutation spectrum of genes related to DD/ID and indicate that exome-based CNV analysis could improve the diagnostic yield of patients with DD/ID.

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Section: Discussionsupporting

confidence: 88%

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

et al. 2021

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“…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.…”

Section: Introductionmentioning

confidence: 57%

“…Our study demonstrates that variant-specific functional follow-up is crucial to understand biological underpinnings of overlapping phenotypes and heterogeneity within cohorts. Work from our group and others have previously delineated the phenotypic heterogeneity within cohorts carrying germline SETBP1 loss-of-function variants causing SETBP1 haploinsufficiency disorder, which have much milder clinical correlates than classical SGS 6,15,16 . Here, we present, to our knowledge, the largest cohort of individuals who have SETBP1 variants (missense and in-frame deletion) outside the canonical degron region, with clinical features that do not fit with the original diagnostic criteria of classical SGS.…”

Section: Discussionmentioning

confidence: 99%

“…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. The main clinical features include moderate-to-severe speech and language impairments, mild motor developmental delay, wide variability in intellectual functioning, hypotonia, vision impairment, and behavioural problems such as attention/concentration deficits and hyperactivity 15,16 . 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 .…”

Section: Introductionmentioning

confidence: 99%

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

Wong

Kampen

Braden

et al. 2022

Preprint

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Germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders. Heterozygous missense variants at a hotspot encoding a canonical degron lead to SETBP1 accumulation and Schinzel-Giedion syndrome (SGS), a rare severe developmental disorder involving multisystem malformations. Heterozygous loss-of-function variants result in SETBP1 haploinsufficiency disorder which is phenotypically much milder than SGS. Following an initial description of four individuals with atypical SGS carrying heterozygous missense variants adjacent to the degron, a few individual cases of variants outside the degron were reported. Due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of the roles of the gene in brain development, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remain elusive, imposing challenges for diagnosis and patient care. Here, we present a comprehensive investigation of the largest cohort to-date of individuals carrying SETBP1 missense variants outside the degron (n=18, including one in-frame deletion). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1 haploinsufficiency disorder, and primarily characterised by intellectual disability, epilepsy, speech and motor impairment. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding and transcription. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care and aetiology of SETBP1-related disorders.

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“…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.…”

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confidence: 99%

A new impact factor for European Journal of Human Genetics

McNeill

2021

Eur J Hum Genet

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Clinical delineation of SETBP1 haploinsufficiency disorder

Cited by 16 publications

References 20 publications

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

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

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

A new impact factor for European Journal of Human Genetics

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