SETD2 – Luscan-Lumish Syndrome

Luscan-Lumish syndrome is an autosomal dominant overgrowth disorder characterized by macrocephaly, postnatal overgrowth, intellectual disability and developmental delay caused by heterozygous SETD2 mutations (PMID:29681085).

Genetic evidence includes 19 unrelated probands harboring de novo SETD2 variants—frameshift, nonsense and missense—distributed throughout the gene (PMID:29681085; PMID:32710489; PMID:37025455; PMID:36777730). No familial segregation beyond de novo occurrence has been reported.

Variant spectrum is dominated by predicted loss-of-function changes, accounting for 68.5% of 51 point mutations (frameshift and nonsense) and supporting a haploinsufficiency model (PMID:37025455). A representative variant is c.5835_c.5836insAGAA (p.Ala1946ArgfsTer2), which truncates the C-terminal SET domain and abolishes H3K36 methyltransferase activity.

Functional studies demonstrate that SETD2 deficiency leads to global loss of histone H3 Lys36 trimethylation and abolishes α-tubulin Lys40 methylation, resulting in defective mitotic spindle dynamics and cytokinesis, concordant with neurodevelopmental phenotypes (PMID:27528705).

Genotype–phenotype correlations reveal that missense variants at codon 1740 produce a distinct microcephaly-severe intellectual disability syndrome, suggesting potential gain-of-function effects for p.Arg1740Trp, distinct from classic Luscan-Lumish features (PMID:32710489).

In summary, de novo heterozygous loss-of-function SETD2 variants cause Luscan-Lumish syndrome via haploinsufficiency of H3K36 and α-tubulin methylation pathways. Key take-home: SETD2 sequencing is essential for diagnosis and genetic counseling in overgrowth-intellectual disability syndromes.

References

• Frontiers in genetics • 2023 • A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy. PMID:37025455
• American journal of medical genetics. Part A • 2018 • Two novel cases expanding the phenotype of SETD2-related overgrowth syndrome. PMID:29681085
• American journal of medical genetics. Part A • 2020 • Genotype-phenotype correlation at codon 1740 of SETD2. PMID:32710489
• Frontiers in genetics • 2023 • Clinical and genetic features of luscan-lumish syndrome associated with a novel de novo variant of SETD2 gene: Case report and literature review. PMID:36777730
• Molecular cancer research : MCR • 2016 • A New Chromatin-Cytoskeleton Link in Cancer. PMID:27528705

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