Submission Details

The SETD2 gene encodes a histone lysine methyltransferase that plays an important role in chromatin-mediated regulation of gene expression. SETD2 can also interact with non-histone substrates and methylate microtubules and actin, thereby regulating cytoskeletal functions. Although protein truncating variants in SETD2 had been observed in a cohort study of individuals with autism spectrum disorder in 2012 (O’Roak et al., PMID: 23160955), the first reports focusing on variants in SETD2 as a cause of autosomal dominant SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth were published in 2014 (Luscan et al., PMID: 24852293) and 2015 (Lumish et al., PMID: 26084711). The term selected for curation includes individuals with Luscan-Lumish syndrome (OMIM# 616831) and Intellectual developmental disorder, autosomal dominant 70 (OMIM# 620157). Affected individuals exhibit developmental delay or intellectual disability, motor delay, speech delay, hypotonia, autism spectrum disorder, and sometimes features such as macrocephaly, overgrowth, and dysmorphic features.

Thirteen variants (7 frameshift, 4 nonsense, 1 recurrent missense, and 1 splice) that have been reported in 15 probands in 12 publications (PMIDs: 23160955, 24852293, 26084711, 27317772, 29681085, 31643139, 32710489, 33248444, 33766796, 36777730, 37025455, 37372360) are included in this curation. Most of the reported variants are de novo. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function. However, the mechanism of the recurrent missense variant (NM_014159.7:c.5219G>A, p.Arg1740Gln) reported in three individuals (PMID: 32710489) remains to be determined. Several other de novo missense variants were not scored given the absence of evidence of pathogenicity (PMIDs: 23160955, 24852293, 31643139, 33248444, 37372360).

Of note, this gene has also been reported in relation to autosomal dominant SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome (MONDO:0035706), which was assessed separately.

This gene-disease relationship is further supported by experimental evidence, including biochemical function and protein interaction studies. Other genes encoding histone lysine methyltransferases have also been implicated in neurodevelopmental disorders, including SETD1A, SETD1B, and SETD5. Furthermore, other genes belonging to the histone methyltransferase family have also been involved in overgrowth disorders (DNMT3A and BRWD3). In addition, POLR2A and TUBA1A, two proteins that interact with SETD2 (PMIDs: 16118227, 27518565), are also implicated in neurodevelopmental disorders.

In summary, there is definitive evidence supporting the relationship between SETD2 and autosomal dominant SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 4, 2023 (SOP Version 9).

The SETD2 gene encodes a histone lysine methyltransferase that plays an important role in chromatin-mediated regulation of gene expression. SETD2 can also interact with non-histone substrates and methylate microtubules and actin, thereby regulating cytoskeletal functions. Although protein truncating variants in SETD2 had been observed in a cohort study of individuals with autism spectrum disorder in 2012 (O’Roak et al., PMID: 23160955), the first reports focusing on variants in SETD2 as a cause of autosomal dominant SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth were published in 2014 (Luscan et al., PMID: 24852293) and 2015 (Lumish et al., PMID: 26084711). The term selected for curation includes individuals with Luscan-Lumish syndrome (OMIM# 616831) and Intellectual developmental disorder, autosomal dominant 70 (OMIM# 620157). Affected individuals exhibit developmental delay or intellectual disability, motor delay, speech delay, hypotonia, autism spectrum disorder, and sometimes features such as macrocephaly, overgrowth, and dysmorphic features.

Thirteen variants (7 frameshift, 4 nonsense, 1 recurrent missense, and 1 splice) that have been reported in 15 probands in 12 publications (PMIDs: 23160955, 24852293, 26084711, 27317772, 29681085, 31643139, 32710489, 33248444, 33766796, 36777730, 37025455, 37372360) are included in this curation. Most of the reported variants are de novo. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function. However, the mechanism of the recurrent missense variant (NM_014159.7:c.5219G>A, p.Arg1740Gln) reported in three individuals (PMID: 32710489) remains to be determined. Several other de novo missense variants were not scored given the absence of evidence of pathogenicity (PMIDs: 23160955, 24852293, 31643139, 33248444, 37372360).

This gene-disease relationship is further supported by experimental evidence, including biochemical function and protein interaction studies. Other genes encoding histone lysine methyltransferases have also been implicated in neurodevelopmental disorders, including SETD1A, SETD1B, and SETD5. Furthermore, other genes belonging to the histone methyltransferase family have also been involved in overgrowth disorders (DNMT3A and BRWD3). In addition, POLR2A and TUBA1A, two proteins that interact with SETD2 (PMIDs: 16118227, 27518565), are also implicated in neurodevelopmental disorders.

Of note, this gene has also been reported in relation to autosomal dominant SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome (MONDO:0035706), which was assessed separately.

In summary, there is definitive evidence supporting the relationship between SETD2 and autosomal dominant SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 4, 2023 (SOP Version 9).