2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Expanding The Genetic and Phenotypic Spectrum of Cohesinopathies in a Single Center

Expanding The Genetic and Phenotypic Spectrum of Cohesinopathies in a Single Center

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The study aimed to expand the understanding of cohesinopathies, a group of rare neurodevelopmental disorders, by identifying disease-causing variants in genes associated with Cornelia de Lange syndrome (CdLS). The researchers conducted a retrospective study involving over 5,000 patients/families who underwent genomic testing to detect genetic variations. A diagnosis of CdLS was confirmed in patients with specific pathogenic variants in genes such as NIPBL, RAD21, SMC3, BRD4, HDAC8, or SMC1A. Additionally, the analysis was extended to other components and regulators of the cohesin complex to identify individuals who may have features of CdLS. Medical records were reviewed to assess clinical and phenotypic characteristics.<br /><br />The findings revealed an expanded genetic heterogeneity associated with CdLS, highlighting the importance of comprehensive pathway analysis in understanding these disorders. Of the 51 patients with private variants, 68% had a molecular diagnostic genotype, with most cohesinopathies attributed to pathogenic variants in NIPBL or ANKRD11. Five patients had variants of unknown significance (VUS) that were considered as a likely-diagnostic genotype. Some individuals had variants in genes not previously associated with cohesinopathy, including loss-of-function variants in JADE2. The study also identified the presence of de novo variants in these patients.<br /><br />The researchers noted that the identified variants in this study were absent in public databases, supporting their potential contribution to cohesinopathy-related disorders. They concluded that further assessment using different testing modalities may uncover additional cases and contribute to the phenotypic expansion of cohesinopathy-related disorders. They also highlighted the need to classify gene panel testing as cohesinopathy-related disorders based on the growing evidence. Overall, the study expands the understanding of the genetic and phenotypic spectrum of cohesinopathies, suggesting the involvement of multiple genes and pathways in these rare neurodevelopmental disorders.

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Co-Author - Isabelle Thiffault, PhD, MsC, FABMGG; Presenting Author - Joseph T. Alaimo, PhD, FACMG; Co-Author - Vitoria Paolillo, PhD; Co-Author - Florencia Del Viso, PhD; Co-Author - Ana SA. Cohen, PhD; Co-Author - Emily G. Farrow, PhD, CGC; Co-Author - Susan Starling, Genetics Counselor; Co-Author - Maggie Humphrey, MS, CGC; Co-Author - Caitlin Schwager, MS, CGC; Co-Author - Lauren Bartik, MsC; Co-Author - Kendra Engleman, MS, CGC; Co-Author - Laura Cross, MS, CGC; Co-Author - Holly Welsh, MS CGC; Co-Author - Eric T. Rush, MD; Co-Author - Shivarajan M. Amudhavalli, MD; Co-Author - Bonnie R. Sullivan, MD; Co-Author - Dihong Zhou, MD; Co-Author - Elizabeth Shaffer, MD; Co-Author - Waseem Baig, MD; Co-Author - Lee Zellmer, MS, CGC; Co-Author - Mary Rindler, MS, CGC; Co-Author - Tricia N. Zion, MS,CGC; Co-Author - Emelia Boillat, BS; Co-Author - Tomi Pastinen, MD, PhD; Co-Author - Carol J. Carol, PhD; Co-Author - Isabelle Thiffault, PhD, MsC, FABMGG;

Meta Tag

Brain/Nervous System

Delineation of Diseases

Dysmorphology

Exome sequencing

Genetic Testing

Genotype-Phenotype Correlations

Inheritance Patterns

Intellectual disability

Molecular Pathophysiology

NextGen Sequencing

Pathogenesis

Phenotype

Phenotypic delineation of disorders

Structure/Function

Variant Detection

Co-Author Isabelle Thiffault, PhD, MsC, FABMGG

Co-Author Vitoria Paolillo, PhD

Co-Author Florencia Del Viso, PhD

Co-Author Ana SA. Cohen, PhD

Co-Author Emily G. Farrow, PhD, CGC

Co-Author Susan Starling, Genetics Counselor

Co-Author Maggie Humphrey, MS, CGC

Co-Author Caitlin Schwager, MS, CGC

Co-Author Lauren Bartik, MsC

Co-Author Kendra Engleman, MS, CGC

Co-Author Laura Cross, MS, CGC

Co-Author Holly Welsh, MS CGC

Co-Author Eric T. Rush, MD

Co-Author Shivarajan M. Amudhavalli, MD

Co-Author Bonnie R. Sullivan, MD

Co-Author Dihong Zhou, MD

Co-Author Elizabeth Shaffer, MD

Co-Author Waseem Baig, MD

Co-Author Lee Zellmer, MS, CGC

Co-Author Mary Rindler, MS, CGC

Co-Author Tricia N. Zion, MS,CGC

Co-Author Emelia Boillat, BS

Co-Author Tomi Pastinen, MD, PhD

Co-Author Carol J. Carol, PhD

Presenting Author Joseph T. Alaimo, PhD, FACMG

Keywords

cohesinopathies

neurodevelopmental disorders

Cornelia de Lange syndrome

genetic variations

pathogenic variants

comprehensive pathway analysis

genetic heterogeneity

variants of unknown significance

de novo variants

phenotypic spectrum