Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Kayumi, Sayaka; Pérez-Jurado, Luís A.; Palomares, María; Rangu, Sneha; Sheppard, Sarah E.; Chung, Wendy K.; Kruer, Michael C.; Kharbanda, Mira; Amor, David J.; McGillivray, George; Cohen, Julie S.; García‐Miñaúr, Sixto; Eyk, Clare L. van; Harper, Kelly; Jolly, Lisa; Webber, Dani L.; Barnett, Christopher; Santos‐Simarro, Fernando; Pacio‐Míguez, Marta; Pozo, Ángela del; Bakhtiari, Somayeh; Deardorff, Matthew A.; Dubbs, Holly; Izumi, Kosuke; Grand, Katheryn; Gray, Christopher; Mark, Paul R.; Bhoj, Elizabeth; Liu, Dong; Ortiz-González, Xilma R.; Keena, Beth; Zackai, Elaine H.; Goldberg, Ethan M.; Nanclares, Guiomar Pérez de; Pereda, Arrate; Llano-Rivas, Isabel; Arroyo, Ignacio; Fernández-Cuesta, María Ángeles; Thauvin‐Robinet, Christel; Faivre, Laurence; Garde, Aurore; Mazel, Benoît; Bruel, Ange‐Line; Tress, Michael L.; Brilstra, Eva H.; Fine, Amena Smith; Crompton, Kylie Elizabeth; Stegmann, Alexander P.A.; Sinnema, Margje; Stevens, Servi J.C.; Nicolai, Joost; Lesca, Gaëtan; Lion‐François, Laurence; Haye, Damien; Chatron, Nicolas; Piton, Amélie; Nizon, Mathilde; Cogné, Benjamin; Srivastava, Siddharth; Bassetti, Jennifer A.; Muss, Candace; Gripp, Karen W.; Procopio, Rebecca; Millan, Francisca; Morrow, Michelle M.; Assaf, Melissa; Moreno-De-Luca, Andrés; Joss, Shelagh; Hamilton, Mark J. D.; Bértoli, Marta; Foulds, Nicola; McKee, Shane; MacLennan, Alastair H.; Gécz, Jozef; Corbett, Mark

doi:10.1016/j.gim.2022.08.006

Cited by 14 publications

(31 citation statements)

References 49 publications

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“…Accordingly, 10/120 (8.3%) cases had a CHD diagnosis (Table 1). 3,[13][14][15][16] Overall, septal defects, PV anomaly, ToF, and anomalous pulmonary venous return have been reported. 3 Of note, a study by Morton et al 17 evaluating the frequency of damaging variants in cancer risk genes among a large series of patients with CHDs, revealed three further CTNNB1-NEDSDV cases affected by heart defects.…”

Section: Discussionmentioning

confidence: 99%

Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness

et al. 2023

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CTNNB1 [OMIM *116806] encodes β‐catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management.

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Section: Discussionmentioning

confidence: 99%

Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness

et al. 2023

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“…The genetic causes of cerebral palsy are highly heterogeneous, with both meta-analyses (of mostly the same cohorts) finding that the most frequent genetic cause, variation in CTNNB1 , still only accounted for 4% of monogenic cases. Children with CTNNB1 neurodevelopmental disorder have a relatively homogeneous clinical presentation, with frequent truncal hypotonia and nonprogressive peripheral spasticity or hypertonia . Careful rephenotyping of patients with CTNNB1 variation demonstrates that even children with the same highly clinically homogeneous presentation are seen differently by different clinicians, with some given a cerebral palsy diagnosis and some not .…”

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confidence: 99%

“…Children with CTNNB1 neurodevelopmental disorder have a relatively homogeneous clinical presentation, with frequent truncal hypotonia and nonprogressive peripheral spasticity or hypertonia . Careful rephenotyping of patients with CTNNB1 variation demonstrates that even children with the same highly clinically homogeneous presentation are seen differently by different clinicians, with some given a cerebral palsy diagnosis and some not . Early genomic testing in these patients, irrespective of initial clinical diagnosis, can prevent a diagnostic odyssey, with more than half of individuals for whom data were available undergoing a targeted single gene or gene panel before eventually receiving a diagnosis from exome or genome sequencing .…”

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confidence: 99%

“…Careful rephenotyping of patients with CTNNB1 variation demonstrates that even children with the same highly clinically homogeneous presentation are seen differently by different clinicians, with some given a cerebral palsy diagnosis and some not . Early genomic testing in these patients, irrespective of initial clinical diagnosis, can prevent a diagnostic odyssey, with more than half of individuals for whom data were available undergoing a targeted single gene or gene panel before eventually receiving a diagnosis from exome or genome sequencing . As the article by Gonzalez-Mantilla et al concludes, these data provide sufficient evidence to support the inclusion of genomic sequencing as a first-tier test for individuals with cerebral palsy, regardless of their comorbidities and risk factors.…”

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confidence: 99%

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All Patients With a Cerebral Palsy Diagnosis Merit Genomic Sequencing

Eyk

MacLennan

2023

JAMA Pediatr

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“…The identi cation of the genetic component of CP could lead to an improved mechanistic understanding, advance protective interventions, and facilitate the development of therapeutics. Recently, a number of whole-exome sequencing (WES) studies have made encouraging progress in identifying a spectrum of causative genetic variants that contribute to monogenic CP [17][18][19][20] . However, current WES studies focus on only pathogenic variants, which explain a limited fraction of the heritability in CP.…”

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confidence: 99%

Exome-wide association study identified genetic variants contributing to the risk of cerebral palsy

Xing

Cheng

et al. 2022

Preprint

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Cerebral palsy (CP) is the most common physical disability in childhood that results from the interaction of environmental and genetic factors. Yet in many patients, the etiology remains unknown. We identified significant association at rs3131787 within the human leukocyte antigen (HLA) region using two-stage association study between 1,090 CP cases and 1,100 controls. Fine mapping of the HLA region indicated that the carrier frequency of HLA-B*13:02 was significantly higher in CP, particularly in CP without preterm birth, low birth weight, birth asphyxia or periventricular leukomalacia (PVL). DRB1*07:01/DQA1*02:01 was also significantly enriched in CP and more specifically in dyskinetic type. Additionally, significant enrichment of carrier frequency was detected for HLA-A*32:01 in CP with either preterm birth or low birth weight and for HLA-B*27:05 in CP with birth asphyxia. These data suggest that immune dysregulation resulting from immunogenetic variants or environmental exposures may underlie the pathogenesis of CP.

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Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Cited by 14 publications

References 49 publications

Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness

Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness

All Patients With a Cerebral Palsy Diagnosis Merit Genomic Sequencing

Exome-wide association study identified genetic variants contributing to the risk of cerebral palsy

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