CRADD – Intellectual Disability, Autosomal Recessive 34

CRADD is a death‐domain‐containing adaptor in the PIDDosome complex that activates caspase-2 to drive neuronal apoptosis during neocortical development. Biallelic CRADD variants have been linked to a thin lissencephaly (TLIS) variant with megalencephaly, frontal‐predominant pachygyria, epilepsy and intellectual disability, designated autosomal recessive intellectual disability 34.

To date, six affected individuals from four unrelated consanguineous families have been reported with homozygous CRADD variants in the death domain region ([PMID:27773430]). All cases exhibit autosomal recessive inheritance with intellectual disability and characteristic anterior‐predominant pachygyria. Segregation data are limited to the probands, with no additional affected relatives reported.

Variant spectrum includes missense substitutions clustering in the death domain, such as c.491T>G (p.Phe164Cys), and frameshift alleles disrupting the N‐terminal CARD domain, indicating both loss‐of‐function and dominant‐negative mechanisms. No recurrent or population‐specific founder alleles have been described to date.

Functional assays demonstrate that TLIS‐associated CRADD variants do not abrogate PIDD or caspase‐2 binding but abolish caspase-2 activation, resulting in reduced neuronal apoptosis in vitro ([PMID:27773430]). Homozygous Cradd knockout mice phenocopy human megalencephaly and seizures without gross lamination defects, supporting a pathogenic mechanism of defective programmed cell death ([PMID:27773430]).

Biochemical studies of CRADD death domain variants G128R, F164C, R170C and R170H reveal disrupted caspase-2 activation platforms, underlining the critical role of PIDDosome signaling in cortical sculpting and cognitive development ([PMID:30281648]).

Integration of genetic and experimental findings provides strong evidence (ClinGen "Strong") for CRADD as the causative gene in autosomal recessive intellectual disability 34. Defective apoptosis due to loss of CRADD function underpins cortical malformation and intellectual impairment. Key Take-home: CRADD screening is recommended in individuals with autosomal recessive ID and anterior‐predominant pachygyria to inform diagnosis and family counseling.

References

• American Journal of Human Genetics • 2016 • Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant. PMID:27773430
• PLoS One • 2018 • RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS). PMID:30281648

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