Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition

Deliu, Elena; Arecco, Niccolò; Morandell, Jasmin; Dotter, Christoph P.; Contreras, Ximena; Girardot, Charles; Käsper, Eva-Lotta; Kozlova, Alena A.; Kishi, Kasumi; Chiaradia, Ilaria; Noh, Kyung‐Min; Novarino, Gaia

doi:10.1038/s41593-018-0266-2

Cited by 80 publications

(137 citation statements)

References 82 publications

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“…Considering our multi-hit model, further work will be needed to define the relative contribution for each mutation: the FEZF2 mutation, one to three mutations in ASD high-risk genes, and one (or no) de novo SNVs identified in FEZF2 allele-linked families (Figure 7C). For some ASD high-risk genes, such as CDH8, SCN2A and SERD2, their haploinsufficiency in mice is sufficient to induce autistic-like phenotypes as demonstrated for CHD8 (57,58), SCN2A (46), and SETD5 (59). In our case, novel mouse models that can integrate the mutations reported here can be instrumental to dissect the contribution of each mutation to phenotypes relevant of ASD.…”

Section: Discussionsupporting

confidence: 51%

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Bensaid

Loe-Mie

Lepagnol-Bestel

et al. 2019

Preprint

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words)Autism Spectrum Disorders (ASDs) are a heterogeneous collection of neurodevelopmental disorders with a strong genetic basis. Recent studies identified that a single hit of either a de novo or transmitted gene-disrupting, or likely gene-disrupting, mutation in a subset of 65 strongly associated genes can be sufficient to generate an ASD phenotype. We took advantage of consanguineous families with an ASD proband to evaluate this model. By a genome-wide homozygosity mapping of ten families with eleven children displaying ASD, we identified a linkage region of 133 kb in five families at the 3p14.2 locus that includes FEZF2 with a LOD score of 5.8 suggesting a founder effect. Sequencing FEZF2 revealed a common deletion of four codons. However, the damaging FEZF2 mutation did not appear to be sufficient to induce the disease as non-affected parents also carry the mutation and, similarly, Fezf2 knockout mouse embryos electroporated with the mutant human FEZF2 construct did not display any obvious defects in the corticospinal tract, a pathway whose development depends on FEZF2. We extended the genetic analysis of these five FEZF2-linked families versus five FEZF2 non-linked families by studying de novo and transmitted copy number variation (CNV) and performing Whole Exome Sequencing (WES). We identified damaging mutations in the subset of 65 genes strongly associated with ASD whose co-expression analysis suggests an impact on the prefrontal cortex during the mid-fetal periods. From these results, we propose that both FEZF2 deletion and multiple hits in the repertoire of these 65 genes are necessary to generate an ASD phenotype. Significance Statement (120 words)The human neocortex is a highly organized laminar structure with neuron positioning and identity of deep-layer cortical neurons that depend on key transcription factors, such as FEZF2, SATB2, TSHZ3 and TBR1. These genes have a specific spatio-temporal pattern of expression in human midfetal deep cortical projection neurons and display mutations in patients with Autism Spectrum Disorder (ASD). Here, we identified a linkage region involving FEZF2 gene in five consanguineous families with an ASD proband. For these FEZF2-allele linked probands, we identified a four-codon deletion in FEZF2 and damaging mutations in other high-risk ASD genes, that exhibit regional and cell type-specific convergence in neocortical deep-layer excitatory neurons, suggesting a multi-hit genomic architecture of ASD in these consanguineous families.

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Section: Discussionsupporting

confidence: 51%

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Bensaid

Loe-Mie

Lepagnol-Bestel

et al. 2019

Preprint

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“…Our study findings suggest that SETD5 pathogenic variants, akin to what has already been observed in CdL-like phenotypes, can cause a phenotypic spectrum overlapping with KBGS. Interestingly, the ANKRD11 and SETD5 proteins physically interact at the molecular level as demonstrated by spectrometry assays performed in mouse embryonic stem cells and mouse neural progenitor cells (12). Moreover, both proteins interact with HDAC3, a key regulator of histone acetylation/deacetylation balance (8,12).…”

Section: Discussionmentioning

confidence: 98%

“…SETD5, located on chromosome 3p25, encodes for a putative methyltransferase, and belongs to the "writers" group of epigenetic ID genes (11). The gene is widely expressed across the brain, where it regulates gene transcription through its interaction with the histone deacetylase 3 (HDAC3) and RNA polymerase II associated factor 1 (PAF1) complexes (12). SETD5 is also the strongest candidate gene of the 3p25 microdeletion syndrome, as patients harboring either heterozygous SETD5 LoF mutations or 3p25 microdeletions spanning SETD5 show an overlapping phenotype.…”

Section: Introductionmentioning

confidence: 99%

SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome

et al. 2020

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Mendelian disorders of the epigenetic machinery (MDEMs), also named chromatin modifying disorders, are a broad group of neurodevelopmental disorders, caused by mutations in functionally related chromatin genes. Mental retardation autosomal dominant 23 (MRD23) syndrome, due to SETD5 gene mutations, falls into this group of disorders. KBG syndrome, caused by ANKRD11 gene haploinsufficiency, is a chromatin related syndrome not formally belonging to this category. We performed high resolution array CGH and trio-based WES on three molecularly unsolved patients with an initial KBGS clinical diagnosis. A de novo deletion of 116 kb partially involving SETD5 and two de novo frameshift variants in SETD5 were identified in the patients. The clinical re-evaluation of the patients was consistent with the molecular findings, though still compatible with KBGS due to overlapping phenotypic features of KBGS and MRD23. Careful detailed expert phenotyping ascertained some facial and physical features that were consistent with MRD23 rather than KBGS. Our results provide further examples that loss-of-function pathogenic variants in genes encoding factors shaping the epigenetic landscape, lead to a wide phenotypic range with significant clinical overlap. We recommend that clinicians consider SETD5 gene haploinsufficiency in the differential diagnosis of KBGS. Due to overlap of clinical features, careful and detailed phenotyping is important and a large gene panel approach is recommended in the diagnostic workup of patients with a clinical suspicion of KBGS.

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“…SETD5 is highly expressed in the brain, 14 but the underlying mechanism linking its mutations to neurodevelopmental disorders is still unclear. At different developmental stages, this gene exhibits a high level of expression in the cerebral cortex 14,16 . Studies using animal models have corroborated that SETD5 haploinsufficiency causes physical/cognitive abnormalities, and the complete loss of the gene product leads to embryonic lethality 16,17 .…”

Section: Figurementioning

confidence: 99%

Expanding the role of SETD5 haploinsufficiency in neurodevelopment and neuroblastoma

Pires

Tolezano

Costa

et al. 2020

Pediatric Blood & Cancer

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Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition

Cited by 80 publications

References 82 publications

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome

Expanding the role of SETD5 haploinsufficiency in neurodevelopment and neuroblastoma

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