SETD2

Gene Facts

• HGNC Symbol: SETD2 (HGNC:18420)
• HGNC Name: SET domain containing 2, histone lysine methyltransferase
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: HYPB, HIF-1, KIAA1732, FLJ23184, KMT3A
• %HI: 8.64
• pLI: 1
• LOEUF: 0.18
• Cytoband: 3p21.31
• Genomic Coordinates:

  GRCh37/hg19:	chr3:47057926-47205603
  GRCh38/hg38:	chr3:47016436-47164840

• MANE Select Transcript: NM_014159.7 ENST00000409792.4
• Function: Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate (PubMed:16118227, PubMed:19141475, PubMed:21526191, PubMed:21792193, PubMed:23043551, PubMed:27474439). It is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro (PubMed:19332550). Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation (By similarity). Plays a role in chromatin structure modu... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-13427
• ClinGen Curation ID: CCID:007831
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Uncertain
• Last Evaluated: 03/08/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Complex Neurodevelopmental Disorder

HI Evidence

• PUBMED: 24852293
  Luscan et al (2014): Targeted NGS study of 22 methylation-related genes in 16 patients with features Sotos-like and Weaver syndrome. A nonsense variant (p.Gln274*) was found in an adopted 7yr old girl referred for speech delay, overgrowth and being overweight. Patient also had frequent ear and renal infections without any associated malformations.
• PUBMED: 26084711
  Lumish et al (2015): WES on a trio identified a de novo frameshift variant (c.2028delT, p.677LfsX19) in a 17yr old girl with autism spectrum disorder (ASD), developmental delay, intellectual disability, behavioral compulsions, aggressiveness, anxiety disorder, attention deficit-hyperactivity disorder, generalized tonic-clonic seizures starting at 10 years of age, Chiari I malformation, mild to moderate hydrocephalus of the third and lateral ventricles, progressive macrocephaly, syringomyelia, and short stature.
• PUBMED: 27317772
  Tlemsani et al (2016): Targeted NGS of DNMT3A & SETD2 in 210 NSD1 mutation negative, Sotos-like patients. A de novo frameshift variant (c.5285_5286 delAC, p.His1762Leufs*26) was found in a 12yr old boy referred for ID, tall stature, macrocephaly, dysmorphia, café-au-lait spots and hyperchromic spots following the lines of Blaschko. Also, neonatal hypotonia, feedings difficulties, psychomotor delay, no meaningful communication at 12 yrs. Of note: younger sister without the SETD2 variant but with tall stature (+2 SD), macrocephaly (+2.3 SD) and Blaschkoid skin spots on arms. No hypotonia at birth and was able to walk at 15 months. Able to speak with sentences at 3 years. Mild learning difficulties but no ID (IQ 95). Not dysmorphic.
• PUBMED: 29681085
  Van Rij et al. (2018) report on two novel patients diagnosed with SETD2-related overgrowth syndrome: a 4.5-year-old boy and a 23-year-old female adolescent with a speech and language developmental delay, autism spectrum disorder and macrocephaly. Both had de novo frameshift variants in the SETD2 gene. Features not previously described which were present in either one of our patients were nasal polyps, a large tongue with creases, a high pain threshold, constipation, and undescended testicles.
• PUBMED: 31643139
  Marzin et al. (2019) report 4 new patients with variants in SETD2, including 2 nonsense (unknown inheritance) and review nine earlier reported patients. Almost all patients presented with macrocephaly associated with advanced stature and obesity in half of the cases. In addition to these principal manifestations, neurodevelopmental disorders are common such as intellectual disability (83%), autism spectrum disorders (89%), and behavioral difficulties (100%) with aggressive outbursts (83%). A variety of features such as joint hypermobility (29%), hirsutism (33%), and naevi (50%) were also reported. Identified variants are intragenic loss-of-function variants with truncating (69%) and missense (31%) variants.
• PUBMED: 24901346
  Iglesias et al. (2014) describe the results of exome sequencing of 115 pts at GeneDx, mostly children (78.9%). The most common indications for testing were birth defects (24.3%) and developmental delay (25.2%). The authors report 1 de novo frame shift variant in a patient with DD, short stature, Chiari malformation, macrocephaly.

• HI Evidence Comments: Assertions have been made in the literature that variation in SETD2 is associated with Luscan-Lumish syndrome, a condition characterized by neurodevelopmental disorders and overgrowth. However, several cases of putative loss of function variants have been reported in this gene in individuals without overgrowth but with neurodevelopmental disorders. As the neurodevelopmental presentations appear to be the most consistent piece of this phenotype at this time, we have opted to curate under the term "complex neurodevelopmental disorder." Additional information is needed to clarify the full phenotypic spectrum associated with this gene. Additional evidence includes: PMID 30919572 -- Al-Dewik et al (2019) reviewed exome sequencing data on 509 patients with different clinical indications and found an in-frame insertion (c.6725_6736del12insTGTGAT) which resulted in p.A2242VfsX2 in a patient with macrocephaly, intellectual disability, and dysmorphic features. The inheritance of this variant was unknown. PMID 23160955 -- O'Roak et al (2012): Exome sequencing candidate gene study of 2446 ASD probands from the Simons Simplex Collection. Identified a de novo frameshift variant (p.Asn2114IlefsX33) in 1 female with autism. In addition, male participants with autism were found to have inherited nonsense variants ( p.Gln7X & p.Cys394X). PMID 31785789 -- Tuner et al (2019) reviewed 8,825 exome sequencing trios and identified 3 de novo frameshift and 1 de novo splicing variant in patients with developmental disorder or ASD. PMID 32094838 -- Husson et al (2020) reported on exome sequencing from 253 cases, including patients from whom parental DNA was available (n = 159) and 94 randomly selected patients. A de novo nonsense variant (p.Arg1708* c.5122C>T) was identified in a patient with Asperger syndrome. PMID 33004838 -- Wang et al (2020) performed next generation sequencing on 63 genes in 16,294 NDD cases, and an additional 62 genes in 6,211 NDD cases. Altogether, they evaluated a total of 125 genes in over 16,000 NDD cases. The authors identified a splicing ( c.4715+1G>A) and frame shift (c.4210delC) in 2 patients; inheritance of these variants was unknown. PMID 30559488 -- Coe et al (2019) did meta-analysis of 10927 NDD cases (ASD, ID or DD) and found 5 de novo likely gene-disruptive (LGD) variants including 1 frame shift variant in 2 patients with ASD and 3 patients with ID/DD, all de novo. Decipher ExAC pLI: 1.00, Decipher HI=8.64 (<10). However, GnomAD listed 29 LOF variants, and there are 3 full/large partial deletions of this gene in DGV. Also, 2 autism patients with inherited SETD2 LOF variants (O'Roak et al (2012).

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: No evidence found.