Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations

Elizabeth A Werren; Emily R Peirent; Henna Jantti; Alba Guxholli; Kinshuk Raj Srivastava; Naama Orenstein; Vinodh Narayanan; Wojciech Wiszniewski; Mateusz Dawidziuk; Pawel Gawlinski; Muhammad Umair; Amjad Khan; Shahid Niaz Khan; David Geneviève; Daphné Lehalle; K L I van Gassen; Jacques C Giltay; Renske Oegema; Richard H van Jaarsveld; Rafiullah Rafiullah; Gudrun A Rappold; Rachel Rabin; John G Pappas; Marsha M Wheeler; Michael J Bamshad; Yao-Chang Tsan; Matthew B Johnson; Catherine E Keegan; Anshika Srivastava; Stephanie L Bielas

doi:10.1038/s41419-024-06768-6

Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations

Cell Death Dis. 2024 May 30;15(5):379. doi: 10.1038/s41419-024-06768-6.

Authors

Elizabeth A Werren^{1

2}, Emily R Peirent³, Henna Jantti⁴, Alba Guxholli^{1

5}, Kinshuk Raj Srivastava⁶, Naama Orenstein⁷, Vinodh Narayanan⁸, Wojciech Wiszniewski⁹, Mateusz Dawidziuk¹⁰, Pawel Gawlinski¹⁰, Muhammad Umair^{11

12}, Amjad Khan^{9

13}, Shahid Niaz Khan¹⁴, David Geneviève¹⁵, Daphné Lehalle¹⁶, K L I van Gassen¹⁷, Jacques C Giltay¹⁷, Renske Oegema¹⁷, Richard H van Jaarsveld¹⁷, Rafiullah Rafiullah¹⁸, Gudrun A Rappold¹⁹, Rachel Rabin²⁰, John G Pappas²⁰, Marsha M Wheeler²¹, Michael J Bamshad^{22

23}, Yao-Chang Tsan²⁴, Matthew B Johnson⁴, Catherine E Keegan^{1

5}, Anshika Srivastava^#²⁵, Stephanie L Bielas^#^{26

27}

Affiliations

¹ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
² Advanced Precision Medicine Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CTt, 06032, USA.
³ Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, 48109, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁵ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
⁶ Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
⁷ Schneider Children's Medical Center of Israel, Petah Tikva, 4920235, Israel.
⁸ Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
⁹ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, 97239, USA.
¹⁰ Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
¹¹ Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, 11481, Saudi Arabia.
¹² Department of Life Sciences, School of Science, University of Management and Technology, Lahore, Punjab, 54770, Pakistan.
¹³ Department of Zoology, University of Lakki Marwat, Lakki Marwat, Khyber Pakhtunkhwa, 28420, Pakistan.
¹⁴ Department of Zoology, Kohat University of Science and Technology, Kohat, Pakistan.
¹⁵ Montpellier University, Inserm Unit U1183, Reference Center for Rare Diseases and Developmental Anomalies, CHU, 34000, Montpellier, France.
¹⁶ Sorbonne University, Department of Medical Genetics, Hospital Armand Trousseau, 75012, Paris, France.
¹⁷ Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 EA, The Netherlands.
¹⁸ Department of Biotechnology, Faculty of Life Sciences, BUITEMS, Quetta, 87300, Pakistan.
¹⁹ Department of Human Molecular Genetics, Institute of Human Genetics, Ruprecht-Karls-University, Heidelberg, 69120, Germany.
²⁰ Department of Pediatrics, NYU Grossman School of Medicine, New York, NY, 10016, USA.
²¹ Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA.
²² Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA.
²³ Brotman Baty Institute, Washington, 98195, USA.
²⁴ Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁵ Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India. [email protected].
²⁶ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. [email protected].
²⁷ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. [email protected].

^# Contributed equally.

Abstract

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.

MeSH terms

Alleles
Cell Differentiation / genetics
Child
Child, Preschool
Female
Humans
Intellectual Disability* / genetics
Intellectual Disability* / pathology
Male
Malformations of Cortical Development / genetics
Malformations of Cortical Development / pathology
Membrane Proteins* / genetics
Membrane Proteins* / metabolism
Neurodevelopmental Disorders / genetics
Tumor Suppressor Proteins

Substances

Membrane Proteins
CSMD1 protein, human
Tumor Suppressor Proteins

Grants and funding

R01AWD010411/U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)