Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations.
Elizabeth A WerrenEmily R PeirentHenna JanttiAlba GuxholliKinshuk Raj SrivastavaNaama OrensteinVinodh NarayananWojciech WiszniewskiMateusz DawidziukPawel GawlinskiMuhammad UmairAmjad KhanShahid Niaz KhanDavid GenevieveDaphné LehalleK L I van GassenJacques C GiltayRenske OegemaRichard H van JaarsveldRafiullah RafiullahGudrun A RappoldRachel RabinJohn G PappasMarsha M WheelerMichael J BamshadYao-Chang TsanMatthew B JohnsonCatherine E KeeganAnshika SrivastavaStephanie L BielasPublished in: Cell death & disease (2024)
CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.
Keyphrases
- intellectual disability
- autism spectrum disorder
- immune response
- early stage
- copy number
- embryonic stem cells
- squamous cell carcinoma
- transcription factor
- zika virus
- multiple sclerosis
- genome wide
- dna methylation
- dendritic cells
- radiation therapy
- neoadjuvant chemotherapy
- rectal cancer
- induced pluripotent stem cells
- inflammatory response