TY - JOUR
T1 - Genotype–phenotype correlation at codon 1740 of SETD2
AU - Rabin, Rachel
AU - Radmanesh, Alireza
AU - Glass, Ian A.
AU - Dobyns, William B.
AU - Aldinger, Kimberly A.
AU - Shieh, Joseph T.
AU - Romoser, Shelby
AU - Bombei, Hannah
AU - Dowsett, Leah
AU - Trapane, Pamela
AU - Bernat, John A.
AU - Baker, Janice
AU - Mendelsohn, Nancy J.
AU - Popp, Bernt
AU - Siekmeyer, Manuela
AU - Sorge, Ina
AU - Sansbury, Francis Hugh
AU - Watts, Patrick
AU - Foulds, Nicola C.
AU - Burton, Jennifer
AU - Hoganson, George
AU - Hurst, Jane A.
AU - Menzies, Lara
AU - Osio, Deborah
AU - Kerecuk, Larissa
AU - Cobben, Jan M.
AU - Jizi, Khadijé
AU - Jacquemont, Sebastien
AU - Bélanger, Stacey A.
AU - Löhner, Katharina
AU - Veenstra-Knol, Hermine E.
AU - Lemmink, Henny H.
AU - Keller-Ramey, Jennifer
AU - Wentzensen, Ingrid M.
AU - Punj, Sumit
AU - McWalter, Kirsty
AU - Lenberg, Jerica
AU - Ellsworth, Katarzyna A.
AU - Radtke, Kelly
AU - Akbarian, Schahram
AU - Pappas, John
N1 - Publisher Copyright:
© 2020 Wiley Periodicals LLC
PY - 2020/9/1
Y1 - 2020/9/1
N2 - The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.
AB - The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.
KW - SETD2
KW - clinical genetics
KW - genotype phenotype
KW - histone modification
KW - neurodevelopmental
UR - http://www.scopus.com/inward/record.url?scp=85088400839&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.61724
DO - 10.1002/ajmg.a.61724
M3 - Article
C2 - 32710489
AN - SCOPUS:85088400839
SN - 1552-4825
VL - 182
SP - 2037
EP - 2048
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 9
ER -