Cohesin complex-associated holoprosencephaly
Copyright policy )Cohesin complex-associated holoprosencephaly
AbstractMarked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.
- Boston Children's Hospital United States
- Cleveland Clinic United States
- University of Sheffield United Kingdom
- Erasmus University Rotterdam Netherlands
- Western University Canada
Male, 570, Adolescent, Chromosomal Proteins, Non-Histone, VARIANT, Cohesin complex; Forebrain division; Holoprosencephaly; X-linked inheritance, Cell Cycle Proteins, SMC1A CAUSE, Mice, X-linked inheritance, SONIC-HEDGEHOG, OF-FUNCTION MUTATIONS, Holoprosencephaly, Animals, Humans, Child, Cohesins, EPILEPSY, forebrain division, cohesin complex, DEVELOPMENTAL DELAY, EMC MGC-02-13-02, Infant, Newborn, 500, Infant, Mice, Inbred C57BL, INDIVIDUALS, holoprosencephaly, DE-LANGE-SYNDROME, CORNELIA, Child, Preschool, Medicine, Female, RAD21 MUTATIONS, Cohesin complex, Forebrain division, Structural Maintenance of Chromosome Protein 1
Male, 570, Adolescent, Chromosomal Proteins, Non-Histone, VARIANT, Cohesin complex; Forebrain division; Holoprosencephaly; X-linked inheritance, Cell Cycle Proteins, SMC1A CAUSE, Mice, X-linked inheritance, SONIC-HEDGEHOG, OF-FUNCTION MUTATIONS, Holoprosencephaly, Animals, Humans, Child, Cohesins, EPILEPSY, forebrain division, cohesin complex, DEVELOPMENTAL DELAY, EMC MGC-02-13-02, Infant, Newborn, 500, Infant, Mice, Inbred C57BL, INDIVIDUALS, holoprosencephaly, DE-LANGE-SYNDROME, CORNELIA, Child, Preschool, Medicine, Female, RAD21 MUTATIONS, Cohesin complex, Forebrain division, Structural Maintenance of Chromosome Protein 1
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