RAD21 MUTATIONS IN CDLS (Page 29)

; [What other Cohesin subunit mutations cause CdLS?]

Mutations in SMC1L1 (also known as SMC1A), which encodes a different subunit of the cohesin complex.

; [What is the inheritance pattern of SMC1A mutations in CdLS?]

Variants can be X-linked recessively inherited.

; [What happens when RAD21 is mutated in humans?]

RAD21 mutations result in a congenital phenotype consistent with a "cohesinopathy" – growth retardation, minor skeletal anomalies, and facial features overlapping with CdLS.

; [How do RAD21 mutation phenotypes differ from classical CdLS?]

Unlike children with NIPBL, SMC1A, or SMC3 mutations, individuals with RAD21 mutations have much milder cognitive impairment than those with classical CdLS.

; [Where do the RAD21 mutations act mechanistically?]

At the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impairing cellular DNA damage response and disrupting transcription.

; [What type of RAD21 mutations cause more severe defects?]

Dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings compared to loss-of-function mutations.

; [Which Cohesin subunit variants have been identified in CdLS patients to date?]

Variants in NIPBL, RAD21, SMC1A, and SMC3 have all been identified in many patients with CdLS clinical diagnosis or features