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. SETD2 was first reported in relation to autosomal dominant SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome in 2020 (Rabin et al., PMID: 32710489). Affected individuals exhibit severe global developmental delay and intellectual disability, microcephaly, hypotonia, respiratory insufficiency, failure to thrive, similar dysmorphic facial features and congenital anomalies affecting several organ systems. Other findings may include seizures, hearing loss, ophthalmologic defects, and structural brain abnormalities. Only one missense variant that has been reported in 12 probands with a de novo inheritance, NM_014159.7:c.5218C>T (p.Arg1740Trp), is included in this curation (PMID: 32710489). No functional studies have been performed and the mechanism of pathogenicity is unknown. Two additional de novo missense variants have been reported in two probands (PMID: 37372360) but they are not included in this curation because their pathogenicity remains unclear.

Of note, SETD2 has also been reported in relation to autosomal dominant SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth, 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. In addition, POLR2A and TUBA1A, two proteins that interact with SETD2 (PMIDs: 16118227, 27518565), are also implicated in neurodevelopmental disorders.

In summary, there is strong evidence supporting the relationship between SETD2 and autosomal dominant SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome. However, at present, all genetic evidence is derived from only one recurrent variant reported in a single publication. We will re-evaluate this gene-disease relationship in the future if more variants are reported. 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. SETD2 was first reported in relation to autosomal dominant SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome in 2020 (Rabin et al., PMID: 32710489). Affected individuals exhibit severe global developmental delay and intellectual disability, microcephaly, hypotonia, respiratory insufficiency, failure to thrive, similar dysmorphic facial features and congenital anomalies affecting several organ systems. Other findings may include seizures, hearing loss, ophthalmologic defects, and structural brain abnormalities. Only one missense variant that has been reported in 12 probands with a de novo inheritance, NM_014159.7:c.5218C>T (p.Arg1740Trp), is included in this curation (PMID: 32710489). No functional studies have been performed and the mechanism of pathogenicity is unknown. Two additional de novo missense variants have been reported in two probands (PMID: 37372360) but they are not included in this curation because their pathogenicity remains unclear.

Of note, SETD2 has also been reported in relation to autosomal dominant SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth, 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. In addition, POLR2A and TUBA1A, two proteins that interact with SETD2 (PMIDs: 16118227, 27518565), are also implicated in neurodevelopmental disorders.

In summary, there is strong evidence supporting the relationship between SETD2 and autosomal dominant SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome. However, at present, all genetic evidence is derived from only one recurrent variant reported in a single publication. We will re-evaluate this gene-disease relationship in the future if more variants are reported. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 4, 2023 (SOP Version 9).